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PubMed2005

Age-related human small intestine methylation: evidence for stem cell niches.

BACKGROUND: The small intestine is constructed of many crypts and villi, and mouse studies suggest that each crypt contains multiple stem cells. Very little is known about human small intestines because mouse fate mapping strategies are impractical in humans. However, it is theoretically possible that stem cell histories are inherently written within their genomes. Genomes appear to record histories (as exemplified by use of molecular clocks), and therefore it may be possible to reconstruct somatic cell dynamics from somatic cell errors. Recent human colon studies suggest that random somatic epigenetic errors record stem cell histories (ancestry and total numbers of divisions). Potentially age-related methylation also occurs in human small intestines, which would allow characterization of their stem cells and comparisons with the colon. METHODS: Methylation patterns in individual crypts from 13 small intestines (17 to 78 years old) were measured by bisulfite sequencing. The methylation patterns were analyzed by a quantitative model to distinguish between immortal or niche stem cell lineages. RESULTS: Age-related methylation was observed in the human small intestines. Crypt methylation patterns were more consistent with stem cell niches than immortal stem cell lineages. Human large and small intestine crypt niches appeared to have similar stem cell dynamics, but relatively less methylation accumulated with age in the small intestines. There were no apparent stem cell differences between the duodenum and ileum, and stem cell survival did not appear to decline with aging. CONCLUSION: Crypt niches containing multiple stem cells appear to maintain human small intestines. Crypt niches appear similar in the colon and small intestine, and the small intestinal stem cell mitotic rate is the same as or perhaps slower than that of the colon. Although further studies are needed, age-related methylation appears to record somatic cell histories, and a somatic epigenetic molecular clock strategy may potentially be applied to other human tissues to reconstruct otherwise occult stem cell histories.

Adolescent↗
PubMed2004

Computational prediction of human metabolic pathways from the complete human genome.

BACKGROUND: We present a computational pathway analysis of the human genome that assigns enzymes encoded therein to predicted metabolic pathways. Pathway assignments place genes in their larger biological context, and are a necessary first step toward quantitative modeling of metabolism. RESULTS: Our analysis assigns 2,709 human enzymes to 896 bioreactions; 622 of the enzymes are assigned roles in 135 predicted metabolic pathways. The predicted pathways closely match the known nutritional requirements of humans. This analysis identifies probable omissions in the human genome annotation in the form of 203 pathway holes (missing enzymes within the predicted pathways). We have identified putative genes to fill 25 of these holes. The predicted human metabolic map is described by a Pathway/Genome Database called HumanCyc, which is available at http://HumanCyc.org/. We describe the generation of HumanCyc, and present an analysis of the human metabolic map. For example, we compare the predicted human metabolic pathway complement to the pathways of Escherichia coli and Arabidopsis thaliana and identify 35 pathways that are shared among all three organisms. CONCLUSIONS: Our analysis elucidates a significant portion of the human metabolic map, and also indicates probable unidentified genes in the genome. HumanCyc provides a genome-based view of human nutrition that associates the essential dietary requirements of humans with a set of metabolic pathways whose existence is supported by the human genome. The database places many human genes in a pathway context, thereby facilitating analysis of gene expression, proteomics, and metabolomics datasets through a publicly available online tool called the Omics Viewer.

Arabidopsis↗
PubMed2006

Cellular dynamics of antisense oligonucleotides and short interfering RNAs.

We aim to compare quantitatively the dynamics of the effectiveness of antisense oligonucleotides (AS ODNs) versus short interfering RNAs (siRNAs) and relate their effectiveness to sequence metrics (e.g., predicted free energy of binding). AS ODNs against a quantitative model target, pd1EGFP (destabilized enhanced GFP [green fluorescent protein]), were selected using our thermodynamic model, and siRNA sequences were designed to be identical to the AS ODN sequences in the antisense strand. We evaluated d1EGFP inhibition in transiently and stably transfected Chinese hamster ovary (CHO) cells over time using flow cytometry. Overall, our results show that the rationally designed AS ODN and siRNA sequences proved effective inhibitors of GFP expression and suggest that certain regions of mRNA may be susceptible to both AS ODNs and siRNAs.

Animals↗
PubMed2000

Identification of hereditary hemorrhagic telangiectasia type 1 in newborns by protein expression and mutation analysis of endoglin.

Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder that is heterogeneous in terms of age of onset and clinical manifestations. Endoglin is the gene mutated in HHT1, which is associated with a higher prevalence of pulmonary arteriovenous malformations than HHT2, where ALK-1 is the mutated gene. Endoglin is constitutively expressed on endothelial cells and inducible on peripheral blood activated monocytes so that protein levels can be measured by metabolic labeling and immunoprecipitation. We report the analysis of umbilical vein endothelial cells in 28 newborns from 24 families with a clinical diagnosis of HHT. Reduced levels of endoglin were observed in umbilical vein endothelial cells in 15/28 subjects and in activated monocytes of all clinically affected relatives tested, suggesting that these individuals had HHT1. No mutant protein was expressed at the cell surface in any of these cases, and a transient intracellular species was seen in samples of only two families, supporting a haploinsufficiency model. Quantitative multiplex PCR fragment analysis was established for the endoglin gene and revealed six mutations that were confirmed by automated DNA sequencing. An additional 10 mutations were identified in newborns by sequencing all exons. Of the 16 mutations, 10 were novel, three had been independently identified in related families, and three were previously known. Our data confirm that endoglin levels correlate with the presence or absence of mutation in HHT1 families, allowing the early identification of affected newborns that should be screened clinically to avoid serious complications of this disorder, such as cerebral arteriovenous malformations.

Antigens, CD↗
PubMed1997

Estimates of social consensus by majorities and minorities: the case for social projection.

Meta-analyses of research on consensus estimation have identified an asymmetry in the error patterns between majorities and minorities (Gross & Miller, 1997; Mullen & Hu, 1988). Members of the majority slightly underestimate the size of their own group, whereas members of the minority strongly overestimate the size of theirs. The present analysis shows that a single psychological assumption about projection is sufficient to explain this asymmetry. Most people, regardless of whether they are actually members of the majority or members of the minority, believe themselves to be in the majority. It is not necessary to attribute different psychological mechanisms, such as ego protection or cognitive availability, to majority and minority members. A simple quantitative model and empirical data illustrate this point.

Journal Article↗
PubMed2005

Process analytical technology case study part I: feasibility studies for quantitative near-infrared method development.

This article is the first of a series of articles detailing the development of near-infrared (NIR) methods for solid-dosage form analysis. Experiments were conducted at the Duquesne University Center for Pharmaceutical Technology to qualify the capabilities of instrumentation and sample handling systems, evaluate the potential effect of one source of a process signature on calibration development, and compare the utility of reflection and transmission data collection methods. A database of 572 production-scale sample spectra was used to evaluate the interbatch spectral variability of samples produced under routine manufacturing conditions. A second database of 540 spectra from samples produced under various compression conditions was analyzed to determine the feasibility of pooling spectral data acquired from samples produced at diverse scales. Instrument qualification tests were performed, and appropriate limits for instrument performance were established. To evaluate the repeatability of the sample positioning system, multiple measurements of a single tablet were collected. With the application of appropriate spectral preprocessing techniques, sample repositioning error was found to be insignificant with respect to NIR analyses of product quality attributes. Sample shielding was demonstrated to be unnecessary for transmission analyses. A process signature was identified in the reflection data. Additional tests demonstrated that the process signature was largely orthogonal to spectral variation because of hardness. Principal component analysis of the compression sample set data demonstrated the potential for quantitative model development. For the data sets studied, reflection analysis was demonstrated to be more robust than transmission analysis.

Feasibility Studies↗
PubMed2002

The role of group interest, identity, and stigma in determining mental health policy preferences.

Public attitudes toward mental health present an interesting puzzle. While mental health is one aspect of general health and well-being, it receives less support for government spending increases than does health care. One explanation lies with the stigma that is attached to mental illness. This stigma produces more negative attitudes on policy issues related to persons with mental illness such as government spending for mental health. However, group identification, as defined by personal experience or a family member who has experienced a mental illness, may have a strong effect on these attitudes. Using data from the 1996 General Social Survey's module on mental health. I examine this and other hypotheses and find evidence that group identification increases the likelihood of increased support for government spending for mental health. These robust findings exist even in quantitative models, which include politically relevant variables and measure identification with mental illness in two different ways. These findings suggest that mental health is policy for the few because those most supportive of government spending increases are persons who share the common identity of experiencing mental illness.

Attitude to Health↗
PubMed2004

Cortactin associates with N-cadherin adhesions and mediates intercellular adhesion strengthening in fibroblasts.

The regulation of N-cadherin-mediated intercellular adhesion strength in fibroblasts is poorly characterized; this is due, in part, to a lack of available quantitative models. We used a recombinant N-cadherin chimeric protein and a Rat 2 fibroblast, donor-acceptor cell model, to study the importance of cortical actin filaments and cortactin in the strengthening of N-cadherin adhesions. In wash-off assays, cytochalasin D (1 microM) reduced intercellular adhesion by threefold, confirming the importance of cortical actin filaments in strengthening of N-cadherin-mediated adhesions. Cortactin, an actin filament binding protein, spatially colocalized to, and directly associated with, nascent N-cadherin adhesion complexes. Transfection of Rat-2 cells with cortactin-specific, RNAi oligonucleotides reduced cortactin protein by 85% and intercellular adhesion by twofold compared with controls (P<0.005) using the donor-acceptor model. Cells with reduced cortactin exhibited threefold less N-cadherin-mediated intercellular adhesion strength compared with controls in wash-off assays using N-cadherin-coated beads. Immunoprecipitation and immunoblotting showed that N-cadherin-associated cortactin was phosphorylated on tyrosine residue 421 after intercellular adhesion. While tyrosine phosphorylation of cortactin was not required for recruitment to N-cadherin adhesions it was necessary for cadherin-mediated intercellular adhesion strength. Thus cortactin, and phosphorylation of its tyrosine residues, are important for N-cadherin-mediated intercellular adhesion strength.

Actins↗
PubMed1997

Microtubules suppress actomyosin-based cortical flow in Xenopus oocytes.

Several cell motility processes including cytokinesis and cell locomotion are dependent on the interplay of the microtubule and actomyosin cytoskeletons. However, because such processes are essentially visual phenomena, interactions between the two cytoskeletal systems have been difficult to study quantitatively. To overcome this difficulty, we have developed the Xenopus oocyte as an inducible, quantitative model system for actomyosin-based cortical flow and then exploited the strengths of this system to assess the relationship between microtubules and cortical flow. As in other systems, oocyte cortical flow entails: (1) redistribution of cortical filamentous actin (f-actin); (2) a requirement for actomyosin; (3) redistribution of cell surface proteins; (4) a requirement for cell surface protein mobility; and (5) directed movement of cortical organelles. Cortical flow rate in the oocyte system is inversely proportional to the level of polymeric tubulin and microinjection of free tubulin has no effect on the rate of cortical flow. Enhancement of microtubule polymerization inhibits cortical f-actin cable formation during cortical flow. The effects of microtubule depolymerization on cortical flow are rapid, independent of transcription or translation, independent of effects on the oocyte intermediate filament system, and independent of the upstream stimulus for cortical flow. The results show that the microtubules themselves, or a factor associated with them, suppress cortical flow, either by mechanically resisting flow, or by modulating the actomyosin cytoskeleton.

Actins↗
PubMed2001

Quantitative analysis of the EGF receptor autocrine system reveals cryptic regulation of cell response by ligand capture.

Autocrine signaling is important in normal tissue physiology as well as pathological conditions. It is difficult to analyze these systems, however, because they are both self-contained and recursive. To understand how parameters such as ligand production and receptor expression influence autocrine activity, we investigated a human epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) loop engineered into mouse B82 fibroblasts. We varied the level of ligand production using the tet-off expression system and used metalloprotease inhibitors to modulate ligand release. Receptor expression was varied using antagonistic blocking antibodies. We compared autocrine ligand release with receptor activation using a microphysiometer-based assay and analyzed our data using a quantitative model of ligand release and receptor dynamics. We found that the activity of our autocrine system could be described in terms of a simple ratio between the rate of ligand production (V(LT)) and the rate of receptor production (V(R)). At a V(LT)/V(R) ratio of <0.3, essentially no ligand was found in the extracellular medium, but a significant number of cell receptors (30-40%) were occupied. As the V(LT)/V(R) ratio increased from 0.3 towards unity, receptor occupancy increased and significant amounts of ligand appeared in the medium. Above a V(LT)/V(R) ratio of 1.0, receptor occupancy approached saturation and most of the released ligand was lost into the medium. Analysis of human mammary epithelial cells showed that a V(LT)/V(R) ratio of < 5 x 10(-4)was sufficient to evoke >20% of a maximal proliferative response. This demonstrates that natural autocrine systems can be active even when no ligand appears in the extracellular medium.

Animals↗
PubMed1975

Cell density dependence of the aggregation characteristics of the cellular slime mould Dictyostelium discoideum.

We have measured fruiting body density and spore formation efficiency in Dictyostelium discoideum as functions of initial cell density. Experiments were performed on agar made up with distilled water and on buffered agar. Minor differences are seen; these are discussed. The functions show 4 regions of density dependence which can be accounted for by changes in aggregation characteristics with density and changes in the efficiency of spore differentiation. The results are discussed in terms of the relaying mechanism for signal propagation controlling cell aggregation. They extend earlier measurements by Bonner & Dodd and by Hohl & Raper, supply data for a quantitative model of the aggregation process, allow estimates of signal range, and show the importance of entrainment between neighbouring centres in defining aggregation territories.

Cell Aggregation↗
PubMed2006

Pathways of chemical degradation of polypeptide antibiotic bacitracin.

We described the main pathways of bacitracin (Bc) decomposition, chromatographically set the position of its major degradation products and evaluated microbiological activity of isolated components of Bc and its degradation products. All processes of Bc decomposition under stress and accelerated test conditions were monitored with HPLC, performed mainly on a new type reversed-phase (RP-18e) monolithic silica column (Chromolith) enabling fast separation times and some of them also on conventional HPLC columns. Diode array detection, preparative HPLC and FAB mass spectrometry were used for identification of individual Bc components. We found that the major decomposition mechanism in water solutions of Bc is oxidation, and in alkaline solutions, deamidation. In oxidation process the components B1, B2 and B3 and A are oxidized into their corresponding oxidative products H1, H2, H3 and F respectively by the same mechanism. A detailed study of oxidative degradation products revealed that HPLC separation with an acid mobile phase caused splitting of peaks of components H2, H3 and F into two peaks but the peak of component H1 did not split due to its special structural properties. For the component A we confirmed gradual formation of desamido product through an intermediate. We found oxidative degradation products of Bc to be relatively stable, and desamido degradation products to be rather unstable. The estimation of kinetics of Bc decomposition was presented with a semi-quantitative model. Microbiological activity of individual isolated active components of Bc was established and the negligible antimicrobial activity of the degradation products was confirmed.

Amides↗
PubMed2006

Delayed manifestation and transmission bias of de novo chromosome mutations: their relevance for radiation health effect.

The origin and transmission of de novo chromosome mutations were reviewed on the basis of our chromosome studies in retinoblastoma patients and male infertility. In a series of 264 sporadic retinoblastoma families, gross chromosome rearrangements involving the RB1 locus were identified in 23 cases (8.7%), of which 16 were non-mosaic and 7 were mosaic mutations. The newly formed chromosome mutations, whether they were non-mosaic or mosaic, had a strong bias towards paternally derived chromosome, indicating that they shared a common mechanism where a pre-mutational event or instability is carried over to zygote by sperm and manifested as gross chromosome mutation at the early stages of development. The de novo chromosome mutations are preferentially transmitted through female carriers. This transmission bias is consistent with the finding of higher frequencies of translocation carriers in infertile men (7.69% versus 0.27% in general populations) in whom meiotic progression is severely suppressed, possibly through activation of meiotic checkpoints. Such a meiotic surveillance mechanism may minimize the spreading of newly-arisen chromosome mutations in populations. A quantitative model of meiotic surveillance mechanism is proposed and successfully applied to the published data on ;humped' dose-response curves for radiation-induced spermatogonial reciprocal translocations in several mammalian species.

Animals↗
PubMed1994

Experimental localization of intestinal uptake sites for metals (Cd, Hg, Zn, Se) in vivo in mice.

The intestinal uptake process consists of two separable steps: transport over the luminal membrane into epithelial cytoplasm and transport over the basolateral membrane into serosal fluid. A compound's residence time in mucosal epithelial cytoplasm depends on rates of the two transport processes and, if the rate of the second step is low, on the rate of mucosal sloughing. Using gamma-emitting metal isotopes, in vivo labeling profiles of the intestinal tract were obtained from mice eating their normal diet. The results pertain to processes in the functioning, undisturbed intestinal tract. Single-dose chase experiments indicated that intestinal uptake processes were in fact studied. The labeling profiles varied considerably for different metals. Thus, Cd++ was absorbed mainly in duodenum and early jejunum, while Zn++ was taken up in jejunum and ileum. The uptake profile of Hg++ indicated most rapid uptake in proximal jejunum. Selenomethionine labeled the entire intestinal tract, most rapidly the duodenum, the following intestinal segments were labeled with falling rate. This experimental method is rapid and simple. Further studies aim at developing a quantitative model suited for studying interactions between essential and toxic metals at the level of intestinal metabolism.

Animals↗
PubMed1996

Risk assessment for neurobehavioral toxicity: SGOMSEC joint report.

Behavioral end points for neurotoxicity risk assessment have been developed and examined over the past three decades. They are now ready to move from simple qualitative guidelines, such as exemplified by reference doses, to more quantitative models, such as benchmark doses, based on dose-response information. Risk assessors, confronted by a wider array of methodologies and data than in the past, should be offered guidance in interpretation because now they have to deal with unaccustomed questions and problems. These include reversibility, susceptible populations, multiple end points, and the details of dose-response and dose-effect distributions.

Animals↗
PubMed1983

Influence of intraocular scattered light on lightness-scaling experiments.

Following Munsell's bisection procedure [J. Opt. Soc. Am. 23, 394 (1933)], we established a nine-step gray scale in which each step is an equal increment in lightness. We calculated retinal illuminances after intraocular scatter by using the point-spread function of Vos et al. [Vision Res. 16, 215-219 (1976)]. After this correction for intraocular scatter, we find a logarithmic relationship between retinal illuminance and achromatic lightness scales that are determined by the bisection method. Additional bisection experiments with a series of different backgrounds corroborate this result. We find that lightness depends linearly on the logarithm of scatter-corrected retinal illuminance, with different slopes for backgrounds of different lightness. This study also highlights the importance of using scatter-corrected illuminance in any quantitative model of lightness.

Adult↗
PubMed1983

Simple-opponent receptive fields are asymmetrical: G-cone centers predominate.

For quantitative models of color vision, the R-cone contribution to the r-g channel is less than half of the R-cone contribution to the V lambda channel. There is currently no explanation of how this different contribution of R cones to the two channels comes about. We propose an asymmetrical receptive-field arrangement to explain the difference in weighting. Because cones in receptive-field surrounds are weighted less than cones in centers, placing R cones predominantly in surrounds and G cones in centers provides a simple differential weighting mechanism. Electrophysiological and psychophysical evidence substantiates such an asymmetry of simple-opponent fields.

Animals↗
PubMed1997

Effects of spatial frequency, duration, and contrast on discriminating motion directions.

The minimum speed required for discriminating the direction of drifting gratings was measured at a variety of spatial frequencies, display durations, and contrasts. As was reported previously, speed thresholds were relatively constant for middle and high spatial frequencies, but speed threshold was found to be almost inversely proportional to spatial frequency in the range of 0.25 to 1.0 c/deg. Speed threshold was also found to be inversely proportional to duration between 73 and 40 ms. These results at low frequencies and short durations are shown to be consistent with limits set by the spread of energy in the stimuli, producing velocity uncertainty. A quantitative model of temporal filtering is presented that largely accounts for results at all spatial frequencies and durations by the inclusion of constant positional noise. A discussion includes the possible roles of magnocellular and parvocellular mechanisms in mediating speed thresholds.

Contrast Sensitivity↗