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PubMed1989

Two-compartment dispersion model for analysis of organ perfusion system of drugs by fast inverse Laplace transform (FILT).

A dispersion model developed in chromatographic theory is applied to the analysis of the elution profile in the liver perfusion system of experimental animals. The equation for the dispersion model with the linear nonequilibrium partition between the perfusate and an organ tissue is derived in the Laplace-transformed form, and the fast inverse Laplace transform (FILT) is introduced to the pharmacokinetic field for the manipulation of the transformed equation. By the analysis of the nonlinear least squares method associated with FILT, this model (two-compartment dispersion model) is compared to the model with equilibrium partition between the perfusate and the liver tissue (one-compartment dispersion model) for the outflow curves of ampicillin and oxacillin from the rat liver. The model estimation by Akaike's information criterion (AIC) suggests that the two-compartment dispersion model is more proper than the one-compartment dispersion model to mathematically describe the local disposition of these drugs in the perfusion system. The blood space in the liver, VB, and the dispersion number DN are estimated at 1.30 ml (+/- 0.23 SD) and 0.051 (+/- 0.023 SD), respectively, both of which are independent of the drugs. The efficiency number, RN, of ampicillin is 0.044 (+/- 0.049 SD) which is significantly smaller than 0.704 (+/- 0.101 SD) of oxacillin. The parameters in the two-compartment dispersion model are correlated to the recovery ratio, FH, mean transit time, tH, and the relative variance, sigma 2/t-2H, of the elution profile of drugs from the rat liver.

Ampicillin↗
PubMed2001

Modulation of graft-versus-tumor effects in a murine allogeneic bone marrow transplantation model by tumor-derived transforming growth factor-betaI.

Although graft-versus-leukemia effects in allogeneic bone marrow transplantation (alloBMT) are well documented, graft-versus-tumor (GVT) effects are poorly defined. To investigate the latter, we established a murine model of breast cancer using TS/A, a transforming growth factor (TGF)-beta1-secreting breast cancer cell line of BALB/c origin. In the setting of disparate (parent into F1) alloBMT, no appreciable GVT was identified. To assess whether TGF-beta1 secreted by the tumor might inhibit the antitumor response, TGF-beta1 antisense vector was transfected into the TS/A breast cancer cell line. Mice were inoculated with either TGF-beta1 antisense transfected or the mock transfected cell line and underwent syngeneic or alloBMT. No evidence of GVT was appreciated for the mock-transfected breast cancer cell line as assessed by an absence of a statistically significant difference in survival between syngeneic and alloBMT groups. However, there was a highly statistically significant survival difference between allogeneic versus syngeneic bone marrow transplantation groups inoculated with the TGF-beta1 antisense-transfected cell line (P = .00001) as well as when comparing the survival of mice that received alloBMT for TGF-beta1 antisense-transfected tumor versus mock-transfected tumor (P = .0008). These data suggest that (1) GVT exists against the antisense-transfected breast cancer cells in this experimental model and (2) TGF-beta1 may be involved in suppressing antitumor responses in the setting of alloBMT for breast cancer.

Animals↗
PubMed2001

The TEL/PDGFbetaR fusion in chronic myelomonocytic leukemia signals through STAT5-dependent and STAT5-independent pathways.

The TEL/PDGFbetaR gene, which encodes a fusion protein containing the ETS-family member TEL fused to the protein-tyrosine kinase domain of the platelet-derived growth factor receptor-beta (PDGFbetaR), confers interleukin 3 (IL-3)-independent growth on Ba/F3 hematopoietic cells. TEL/PDGFbetaR mutants have been generated that contain tyrosine-to-phenylalanine (Tyr-->Phe) substitutions at phosphorylation sites present in the native PDGFbetaR to assess the role of these sites in cell transformation by TEL/PDGFbetaR. Similar to previous findings in a murine bone marrow transplantation model, full transformation of Ba/F3 cells to IL-3-independent survival and proliferation required the TEL/PDGFbetaR juxtamembrane and carboxy terminal phosphorylation sites. In contrast to previous reports concerning comparable mutants in the native PDGFbetaR, each of the TEL/PDGFbetaR mutants is fully active as a protein-tyrosine kinase. Expression of the TEL/PDGFbetaR fusion protein causes hyperphosphorylation and activation of signal transducer and activator of transcription (STAT5), and this activation of STAT5 requires the juxtamembrane Tyr579 and Tyr581 in the TEL/PDGFbetaR fusion. Hyperphosphosphorylation of phospholipase Cgamma (PLCgamma) and the p85 subunit of phosphatidylinositol 3-kinase (PI3K) requires the carboxy terminal tyrosine residues of TEL/PDGFbetaR. Thus, full transformation of Ba/F3 cells by TEL/PDGFbetaR requires engagement of PI3K and PLCgamma and activation of STAT5. Taken together with the growth properties of cells transformed by the TEL/PDGFbetaR variants, these findings indicate that a minimal combination of these signaling intermediates contributes to hematopoietic transformation by the wild-type TEL/PDGFbetaR fusion. (Blood. 2001;98:3390-3397)

Animals↗
PubMed2002

Mental tools for thinking about DNA technologies in new ways.

OBJECTIVE: To investigate the nature of creative thinking in biomedical science with specific applications to molecular pathologies and DNA technologies. DATA SOURCES: Accounts of breakthroughs and inventions contained in autobiographies, biographies, interviews, and archival sources. STUDY SELECTION: Discoveries that have altered, or may yet alter, basic textbook accounts of biomedical sciences for which appropriate data sources exist. DATA EXTRACTION: Approximately 1000 data sources were analyzed, both within appropriate sciences and in other creative fields, such as the arts. DATA SYNTHESIS: The current analysis is based on a framework described in our previous book, Sparks of Genius, which outlines a general approach to understanding creative thinking. CONCLUSIONS: Creative thinking in all disciplines depends on a common mental "toolkit" that consists of 13 fundamental tools: observing, imaging, abstracting, pattern recognition, pattern forming, analogizing, body thinking, empathizing, dimensional thinking, modeling, playing, transforming, and synthesizing. Scientists recognize and solve problems by observing data that break the patterns established by theories; exploring a system by creating an abstract model with which they can play; and transforming data into feelings, sounds, and other forms that create surprising analogies to already-understood principles. The result of such personal thinking is knowledge combined with sensation and emotion--feeling and understanding synthesized into complete awareness. We illustrate some of these modes of thinking with reference to recent breakthroughs in DNA-related areas and suggest ways in which the use of "tools for thinking" can increase the probability of making further discoveries in the biomedical sciences.

Biotechnology↗
PubMed1997

Differential immunogenicity of Epstein-Barr virus (EBV) encoded growth transformation-associated antigens in a murine model system.

The strong immunosurveillance of humans against EBV transformed immunoblasts, mediated by CD8+ cytotoxic T cells, is based on the recognition of peptides derived from eight of the nine growth transformation-associated proteins, the nuclear antigens EBNA2-6 and the membrane proteins LMP1, -2A and -2B. The ninth protein, EBNA1, required for maintenance of the viral episomes, and expressed in a cell phenotype independent manner, has not been found to generate a cytotoxic lymphocyte (CTL) response in humans. We tested whether EBNA1 has a similar immunologically privileged status in a species that has not encountered the virus in nature, the mouse. Non-immunogenic murine mammary carcinoma cells were transfected with the appropriate viral gene. Rejection responses were assayed in syngeneic mice following repeated immunisation with irradiated cells. Previously, we found that LMP1 expression in S6C, a murine mammary carcinoma of ACA (H-2f) origin, induces high rejectability, whereas corresponding EBNA1 transfectants remained non-immunogenic. In order to test whether this finding could be reproduced on another MHC class 1 background, we expressed LMP1 and EBNA1 in another non-immunogenic mammary carcinoma, SBfnHd of CBA (H-2k) origin. LMP1 but not EBNA1 transfectants were immunogenic in this system. In order to investigate whether other growth transformation-associated EBV proteins were immunogenic in the mouse, we also transfected the S6C cells with EBNA4, EBNA5, LMP2A and -2B. All four proteins induced strong rejection reactions. These findings are fully consistent with corresponding findings in the human system. They also show that the immunologically privileged status of EBNA1 is not due to some peculiarity of the long-standing co-existence between EBV and the human species, nor to any specific features of the human MHC class I system. They are consistent with the suggestion that EBNA1 may not be properly processed and/or transported, due to specific features of the protein itself.

Animals↗
PubMed2002

Evaluating models of community psychology: social transformation in South Africa.

Tricket (1996) described community psychology in terms of contexts of diversity within a diversity of contexts. As abstract representations of reality, various community psychological models provide further diverse contexts through which to view the diversity of community psychological reality. The Zululand Community Psychology Project is a South African initiative aimed at improving community life. This includes treating the violent sequelae of the unjust Apartheid system through improving relationships among communities divided in terms of historical, colonial, racial, ethnic, political, gender, and other boundaries as well as promoting health and social change. The aim of this article is to evaluate the applicability of various models of community psychology used in this project. The initial quantitative investigation in the Zululand Community Psychology Project involved five coresearchers, who evaluated five community psychology models--the mental health, social action, organizational, ecological, and phenomenological models--in terms of their differential applicability in three partnership centers, representing health, education, and business sectors of the local community. In all three contexts, the models were rank ordered by a representative of each center, an intern community psychologist, and his supervisor in terms of the models' respective applicability to the particular partnership center concerned. Results indicated significant agreement with regard to the differential applicability of the mental health, phenomenological, and organizational models in the health, education, and business centers respectively, with the social action model being most generally applicable across all centers. This led to a further qualitative individual and focus group investigation with eight university coresearchers into the experience of social transformation with special reference to social changes needed in the South African context. These social transformation experiences and perceived changes needed are explicated. Finally, there is discussion with regard to the evaluation of various models of community psychology in international perspective.

Community-Institutional Relations↗
PubMed2006

Determination of peptide and protein ion charge states by Fourier transformation of isotope-resolved mass spectra.

We report an automated method for determining charge states from high-resolution mass spectra. Fourier transforms of isotope packets from high-resolution mass spectra are compared to Fourier transforms of modeled isotopic peak packets for a range of charge states. The charge state for the experimental ion packet is determined by the model isotope packet that yields the best match in the comparison of the Fourier transforms. This strategy is demonstrated for determining peptide ion charge states from "zoom scan" data from a linear quadrupole ion trap mass spectrometer, enabling the subsequent automated identification of singly- through quadruply-charged peptide ions, while reducing the numbers of conflicting identifications from ambiguous charge state assignments. We also apply this technique to determine the charges of intact protein ions from LC-FTICR data, demonstrating that it is more sensitive under these experimental conditions than two existing algorithms. The strategy outlined in this paper should be generally applicable to mass spectra obtained from any instrument capable of isotopic resolution.

Algorithms↗
PubMed2001

Model-based clustering and data transformations for gene expression data.

MOTIVATION: Clustering is a useful exploratory technique for the analysis of gene expression data. Many different heuristic clustering algorithms have been proposed in this context. Clustering algorithms based on probability models offer a principled alternative to heuristic algorithms. In particular, model-based clustering assumes that the data is generated by a finite mixture of underlying probability distributions such as multivariate normal distributions. The issues of selecting a 'good' clustering method and determining the 'correct' number of clusters are reduced to model selection problems in the probability framework. Gaussian mixture models have been shown to be a powerful tool for clustering in many applications. RESULTS: We benchmarked the performance of model-based clustering on several synthetic and real gene expression data sets for which external evaluation criteria were available. The model-based approach has superior performance on our synthetic data sets, consistently selecting the correct model and the number of clusters. On real expression data, the model-based approach produced clusters of quality comparable to a leading heuristic clustering algorithm, but with the key advantage of suggesting the number of clusters and an appropriate model. We also explored the validity of the Gaussian mixture assumption on different transformations of real data. We also assessed the degree to which these real gene expression data sets fit multivariate Gaussian distributions both before and after subjecting them to commonly used data transformations. Suitably chosen transformations seem to result in reasonable fits. AVAILABILITY: MCLUST is available at http://www.stat.washington.edu/fraley/mclust. The software for the diagonal model is under development. CONTACT: kayee@cs.washington.edu. SUPPLEMENTARY INFORMATION: http://www.cs.washington.edu/homes/kayee/model.

Algorithms↗
PubMed2026

The transformative impact of stem cell core facilities in biomedical research.

Over the past three decades, advances in human pluripotent stem cell (hPSC) technologies, including induced pluripotent stem cells, gene editing, and 2D/3D models, have transformed biomedical research. These powerful tools have revolutionized disease modeling, drug discovery, and the development of advanced therapy medicinal products (ATMPs), while driving the establishment of stem cell core facilities. By providing specialized expertise, standardized workflows, and access to advanced technologies, these facilities support both fundamental and translational research, promote rigor and reproducibility, and foster collaboration. This manuscript highlights their role as hubs of excellence and discusses current challenges and future opportunities for the global stem cell community.

Humans↗
PubMed2004

Lung tumour risk in radon-exposed rats from different experiments: comparative analysis with biologically based models.

Data sets of radon-exposed male rats from Wistar and Sprague-Dawley strains have been investigated with two different versions of the two-step clonal expansion (TSCE) model of carcinogenesis. These so-called initiation-promotion (IP) and initiation-transformation (IT) models are named after the cell-based processes that are assumed to be induced by radiation. The analysis was done with all malignant lung tumours taken to be incidental and with fatal tumours alone. For all tumours treated as incidental, both models could explain the tumour incidence data equally well. Owing to its better fit, only the IP model was applied in the analysis of fatal tumours that carry additional information on the time when they cause death. A statistical test rejected the hypothesis that a joint cohort of Wistar and Sprague-Dawley rats can be described with the same set of model parameters. Thus, the risk analysis has been carried out for the Wistar rats and the Sprague-Dawley rats separately and has been restricted to fatal tumours alone because of their similar effect in humans. Using a refined technique of age-adjustment, the lifetime excess absolute risk has been standardised with the survival function from competing risks in the control population. The age-adjusted excess risks for both strains of rats were of similar size, for animals with first exposure later in life they decreased markedly. For high cumulative exposure the excess risk increased with longer exposure duration, for low cumulative exposure it showed the opposite trend. In addition, high cumulative exposure exerted lethal effects other than lung cancer on the rats.

Administration, Inhalation↗
PubMed2004

Model-based optimization of biosurfactant production in fed-batch culture Azotobacter vinelandii.

Fed-batch cultivation of Azotobacter vinelandii 21was optimized for biosurfactant production. Optimization of feed-rate time profile and concentration of nutrient medium components in feeding solution is based on a hybrid mathematical model consisting of mass-balance equations for biomass, biosurfactant, volume of cultural liquid and substrate components: glucose, ammonia nitrogen and phosphate phosphorus. The rate of cultural liquid emulsification activity growth as well as the rates of ammonia nitrogen and phosphate phosphorus consumption is modelled by means of artificial neural network, while the rates of the other biochemical transformations are modelled by adequate kinetic relationships.

Algorithms↗
PubMed2005

Why and how do we model circadian rhythms?

In our attempts to understand the circadian system, we unavoidably rely on abstractions. Instead of describing the behavior of the circadian system in all its complexity, we try to derive basic features from which we form a global concept on how the system works. Such a basic concept is a model of reality. The author discusses why it is advantageous or even necessary to transform conceptual models into mathematical formulations. As examples to demonstrate those advantages, the author reviews 4 types of mathematical models: negative feedback models thought to operate within pacemaker cells, models on coupling between pacemaker cells to generate pacemaker output, oscillator models describing the behavior of the composite circadian pacemaker, and models describing how the circadian pacemaker influences behavior.

Animals↗
PubMed2001

Green fluorescent protein as a reporter for gene expression in the mucoralean fungus Absidia glauca.

Mucoralean fungi (Zygomycota) are used for many industrial processes and also as important model organisms for investigating basic biological problems. Their genetic analysis is severely hampered by low transformation frequencies, by their strong tendency towards autonomous replication of plasmids instead of stable integration, and by the lack of reliable genetic reporter systems. We constructed plasmids for transforming the model zygomycete Absidia glauca that carry the versatile reporter gene coding for green fluorescent protein (GFP). gfp expression is controlled either by the homologous actin promoter or the promoter for the elongation factor of translation, EF1alpha. These plasmids also confer neomycin resistance and carry one of two genetic elements (rag1, seg1) that improve mitotic stability of the plasmid. The gfp constructs were replicated extrachromosomally and could be recovered from retransformed Escherichia coli cells. gfp expression was monitored by epifluorescence microscopy. The gfp reporter gene plasmids presented here for the model zygomycete A. glauca constitute the first reliable system that allows the monitoring of gene expression in this important group of fungi.

Absidia↗
PubMed2026

CeLLTra: aligning cell names with gene expression via a pathway-informed transformer.

MOTIVATION: Single-cell RNA sequencing (scRNA-Seq) technology enables detailed exploration of gene expression at the individual cell level, crucial for annotating cell types and understanding cellular diversity. Traditional methods for cell type annotation often rely on marker genes and manual labeling, posing challenges due to low data quality and incomplete reference datasets. RESULTS: We developed CeLLTra, a novel contrastive learning framework that leverages a Transformer-based model integrating biological pathway information to group genes into super tokens, effectively capturing comprehensive gene expression from scRNA-Seq data. By combining this pathway-informed Transformer with a pretrained domain-specific language model, CeLLTra accurately aligns cell-type annotations with gene expression profiles. Evaluations on a large-scale human scRNA-Seq dataset showed that CeLLTra significantly outperformed state-of-the-art methods in supervised and zero-shot cell-type prediction. Additionally, CeLLTra generalized well to external datasets, improving clustering performance and enabling better characterization of cancerous cell states in tumor-infiltrating myeloid cells from non-small cell lung cancer patients. AVAILABILITY AND IMPLEMENTATION: CeLLTra is freely available on GitHub (https://github.com/WJZheng-group/CeLLTra) and Zenodo (https://doi.org/10.5281/zenodo.17666735). The datasets underlying this article are the following: GSE201333 and GSE127465. All these datasets are publicly available and can be freely accessed on the Gene Expression Omnibus repository.

Humans↗
PubMed1998

A nonlinear isobologram model with Box-Cox transformation to both sides for chemical mixtures.

The linear logistical isobologram is a commonly used and powerful graphical and statistical tool for analyzing the combined effects of simple chemical mixtures. In this paper a nonlinear isobologram model is proposed to analyze the joint action of chemical mixtures for quantitative dose-response relationships. This nonlinear isobologram model incorporates two additional new parameters, Ymin and Ymax, to facilitate analysis of response data that are not constrained between 0 and 1, where parameters Ymin and Ymax represent the minimal and the maximal observed toxic response. This nonlinear isobologram model for binary mixtures can be expressed as [formula: see text] In addition, a Box-Cox transformation to both sides is introduced to improve the goodness of fit and to provide a more robust model for achieving homogeneity and normality of the residuals. Finally, a confidence band is proposed for selected isobols, e.g., the median effective dose, to facilitate graphical and statistical analysis of the isobologram. The versatility of this approach is demonstrated using published data describing the toxicity of the binary mixtures of citrinin and ochratoxin as well as a new experimental data from our laboratory for mixtures of mercury and cadmium.

Algorithms↗
PubMed2000

Computer-based registration for digital subtraction in dental radiology.

OBJECTIVES: (1) To review computerized a posteriori techniques for geometry and contrast registration prior to digital subtraction in dental radiography; (2) to define a uniform notation for their methodological and technical classification and based on this key code; (3) to derive criteria for successful application of computer-based a posteriori registration for routine clinical subtraction. METHODS: All techniques are classified with respect to the (1) dimension of geometry registration; (2) origin; (3) abstraction level, and (4) linkage of features used for registration of geometry; (5) elasticity; (6) domain, and (7) parameter determination of the geometrical transform used; (8) interaction of geometrical registration; as well as (9) origin of features, (10) model of transform, and (11) interaction of procedure for contrast correction. RESULTS: With respect to clinical practicability, superior registration techniques are based on the low level abstraction of intrinsic features for both geometry and contrast registration. By approximately linking the features, a global projective transform should be generated for geometry registration by automatic methods, while automatic contrast correction should be non-parametric. This challenge is met only by one out of 36 published algorithms. Hence, although numerous computer-based techniques have been published, only a few of them are applied more than once in practice. CONCLUSION: The key code proposed in this paper is useful for technical classification of a posteriori registration methods in dental radiography and allows their objective comparison. Further investigations will focus on standardization of practicable procedures to evaluate the robustness of competing methods.

Algorithms↗
PubMed1990

[Prediction system of facial change].

UNLABELLED: Three-dimensional simulation of facial change in a patient with severe facial deformity is very effective in not only determining a treatment plan but also in obtaining informed consent. The purpose of this presentation was to introduce the outline of our prediction system of facial change and its preliminary clinical application. (Outline of this system) This system is composed of the following three parts: Input: Three-dimensional digitized data from modified Moire Topography and coloring data of the face taken by the three-dimensional photographing appliance. ANALYSIS: Reconstruction of colored simulation model and transformation by host computer with 32 bit CPU. Output: Display of full-colored simulation model by three-dimensional graphics (Results of clinical application) 1. Three-dimensional reconstructed graphics were well accepted for clinical use, especially for the prediction in orthognathic surgery. 2. Compared with other systems, the following advantages were found: a) Simplified digitizing system using the CCD camera b) Total access time, from initial data input to display of computed picture, was about 20 minutes c) Accurate reproducibility of facial form and color vision.

Computer Graphics↗
PubMed2004

DNA transport and natural transformation in mesophilic and thermophilic bacteria.

Comparative genome analyses revealed a massive DNA exchange between microbes of distant evolutionary lineages. This phenomenon known as horizontal, or lateral, gene transfer has a tremendous impact in the evolution of prokaryotes. Here, the process of DNA transport via genetic transformation is discussed. This review will focus on the process of DNA uptake mediated by type IV pilin-like proteins in Gram-positive and Gram-negative bacteria. Three tentative models of transformation machineries comprising components similar to proteins of type IV pili and type II secretion are presented. A comparative discussion of the structure of DNA translocators and the underlying mechanism of transfer of free DNA in mesophilic and extremely thermophilic bacteria highlights conserved and distinctive features of the DNA translocators in mesophilic and thermophilic bacteria.

Archaea↗