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PubMedDate not supplied

Effect of different mammographic radiation exposures on predicted benefits of screening for breast cancer.

The benefits and risks of screening for breast cancer, including both mammographic and clinical examinations, are analysed by means of a probabilistic model. The model, applied to previously unpublished data provided by the HIP (Health Insurance Plan of Greater New York) breast cancer screening project, permits more precise stratification by age than previous analyses and allows for incorporation of oncogenic risks due to mammography. It is assumed that, from the tenth year of screening onward, radiation induces 6 cases of breast cancer per year per million women screened per rad delivered to the breast tissue per exam. The predicted pattern of breast cancer cases and deaths is commensurate with that actually observed in the first nine years of the HIP study. In extrapolation to lifetime experience, the model predicts an ultimate decrease in the probability of dying of breast cancer only for women over age fifty at initial screening and an increase in life expectancy for the entire screened group, at an exposure level of three rads per exam. Had radiation dosage been one rad or less per exam, which is within the range now possible with modern equipment and procedures, the radiation risk would not offset even a modest benefit such as is predicted for the younger women, either in number of deaths or years of life expectancy.

Adult↗
PubMed1999

The evolution of exaggerated sexual swellings in primates and the graded-signal hypothesis.

Females of some Old World primate taxa advertise their sexual receptivity with exaggerated sexual swellings. Although a number of hypotheses have been proposed, the function of this conspicuous trait remains unsolved. This review updates information on the phylogenetic distribution of exaggerated swellings and identifies aspects of the morphology, physiology and behaviour of species with this conspicuous trait. Some of these patterns represent new information, while other patterns have been previously identified, but not in ways that control for phylogeny. This review shows that exaggerated swellings are correlated with some features that serve to confuse paternity certainty among males, while other features tend to bias paternity towards more dominant males. Hypotheses for the evolution of exaggerated swellings are then reviewed and critically evaluated. Individually, no single hypothesis can account for all the patterns associated with exaggerated swellings; however, a combination of different hypotheses may explain the contradiction between confusing and biasing paternity. I suggest that exaggerated swellings can be viewed as distributions representing the probability of ovulation (the graded-signal hypothesis). In the context of this probabilistic model, exaggerated swellings enable females to manipulate male behaviour by altering the costs and benefits of mate guarding, so that dominant males tend to guard only at peak swelling, but females can mate with multiple males outside peak swelling to confuse paternity. This hypothesis makes testable predictions for future comparative and observational research. Copyright 1999 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed1997

Prediction of complete gene structures in human genomic DNA.

We introduce a general probabilistic model of the gene structure of human genomic sequences which incorporates descriptions of the basic transcriptional, translational and splicing signals, as well as length distributions and compositional features of exons, introns and intergenic regions. Distinct sets of model parameters are derived to account for the many substantial differences in gene density and structure observed in distinct C + G compositional regions of the human genome. In addition, new models of the donor and acceptor splice signals are described which capture potentially important dependencies between signal positions. The model is applied to the problem of gene identification in a computer program, GENSCAN, which identifies complete exon/intron structures of genes in genomic DNA. Novel features of the program include the capacity to predict multiple genes in a sequence, to deal with partial as well as complete genes, and to predict consistent sets of genes occurring on either or both DNA strands. GENSCAN is shown to have substantially higher accuracy than existing methods when tested on standardized sets of human and vertebrate genes, with 75 to 80% of exons identified exactly. The program is also capable of indicating fairly accurately the reliability of each predicted exon. Consistently high levels of accuracy are observed for sequences of differing C + G content and for distinct groups of vertebrates.

Animals↗
PubMed2001

Helix-helix packing and interfacial pairwise interactions of residues in membrane proteins.

Helix-helix packing plays a critical role in maintaining the tertiary structures of helical membrane proteins. By examining the overall distribution of voids and pockets in the transmembrane (TM) regions of helical membrane proteins, we found that bacteriorhodopsin and halorhodopsin are the most tightly packed, whereas mechanosensitive channel is the least tightly packed. Large residues F, W, and H have the highest propensity to be in a TM void or a pocket, whereas small residues such as S, G, A, and T are least likely to be found in a void or a pocket. The coordination number for non-bonded interactions for each of the residue types is found to correlate with the size of the residue. To assess specific interhelical interactions between residues, we have developed a new computational method to characterize nearest neighboring atoms that are in physical contact. Using an atom-based probabilistic model, we estimate the membrane helical interfacial pairwise (MHIP) propensity. We found that there are many residue pairs that have high propensity for interhelical interactions, but disulfide bonds are rarely found in the TM regions. The high propensity pairs include residue pairs between an aromatic residue and a basic residue (W-R, W-H, and Y-K). In addition, many residue pairs have high propensity to form interhelical polar-polar atomic contacts, for example, residue pairs between two ionizable residues, between one ionizable residue and one N or Q. Soluble proteins do not share this pattern of diverse polar-polar interhelical interaction. Exploratory analysis by clustering of the MHIP values suggests that residues similar in side-chain branchness, cyclic structures, and size tend to have correlated behavior in participating interhelical interactions. A chi-square test rejects the null hypothesis that membrane protein and soluble protein have the same distribution of interhelical pairwise propensity. This observation may help us to understand the folding mechanism of membrane proteins.

Bacterial Proteins↗
PubMed2001

Probabilistic Multidimensional Scaling Using a City-Block Metric.

Using a probabilistic model, exact and approximate probability density functions (PDFs) for city-block distances and distance ratios are developed. The model assumes that stimuli can be represented by random vectors having multivariate normal distributions. Comparisons with the more common Euclidean PDFs are presented. The potential ability of the proposed model to correctly detect Euclidean and city-block metrics is briefly investigated. These results are then contrasted to those obtained using a deterministic, nonmetric model. Copyright 2001 Academic Press.

Journal Article↗
PubMed2027

Inferring Gene Regulatory Networks in Stem Cells: Methods and Applications.

Gene regulatory networks (GRNs) represent the complex interplay of transcription factors, regulatory elements, and target genes that orchestrate cellular identity and function, playing a crucial role in the differentiation and maintenance of stem cells. This chapter provides an overview of experimental and computational methodologies for inferring GRNs, with particular emphasis on single-cell approaches. We first review key experimental techniques for detecting transcription factor binding sites, chromatin accessibility, and DNA motifs, alongside essential databases that support GRN reconstruction. We then introduce computational inference methods that can be categorized into four principal frameworks: correlation-based approaches, regression and machine learning models, probabilistic and deep learning methods, and integrative or message-passing frameworks. To illustrate practical application, we present a case study applying the pySCENIC workflow to a peripheral blood mononuclear cell single-cell RNA sequencing dataset from mouse, demonstrating how regulon-based analysis can reveal cell-type-specific regulatory programs. This chapter aims to serve as a practical guide for researchers seeking to understand and implement GRN inference methodologies in stem cell biology and related fields.

Gene Regulatory Networks↗
PubMed1984

DNA interstrand cross-linking, repair, and SCE mechanism in human cells in special reference to Fanconi anemia.

The relation of DNA cross-linking and repair to sister chromatid exchange (SCE) formation was studied in normal human, Fanconi anemia (FA), and xeroderma pigmentosum (XP) cells. Despite a hypersensitive lethality response in FA cells, the SCE induction rates by mitomycin C (MMC), trimethylpsoralen (TMP)-light, cisplatin, and diepoxybutane were twice as high as in normal cells. For MMC, the induced SCE frequency in normal cells was reduced in a biphasic fashion with a repair incubation time (the first decline t1/2 = 2 hr; the second t1/2 = 14-18 hr) which corresponds exactly to the molecular kinetics of cross-link and monoadduct removal. However, FA cells lack the first half-excision process and exhibit a lack of the first rapid decline SCE component. The slow decline component is present, and a higher SCE frequency is observed 24 to 48 hr after treatment. By contrast, XP cells capable of the half-excision process reveal the first rapid decline component, followed by an extremely slow second-reduction component (t1/2 = 48 hr) due to defective monoadduct repair. The endoreduplication-SCE method revealed that rates of both twin (first cycle) and single (second cycle) SCE formations by MMC and TMP-light were higher in FA cells than in normal cells. These results indicate that cross-links remaining unrepaired induce SCEs as do monoadducts. The probabilistic SCE induction occurs at a rate of 1 SCE per 35 MMC cross-links in FA cells. Further, a non-SCE-forming tolerance mechanism also operates in hypersensitive FA cells. These molecular and cytogenetic results allow us to construct a new probabilistic model for cross-link-induced SCE into which the replication-fork model, random cross-link transfer to both chromatids, and chromatid breakage-reunion are incorporated.

Anemia, Aplastic↗
PubMed1994

Synapses on axon collaterals of pyramidal cells are spaced at random intervals: a Golgi study in the mouse cerebral cortex.

In this study we investigated the arrangement of synapses on local axon collaterals of Golgi-stained pyramidal neurons in the mouse cerebral cortex. As synaptic markers we considered axonal swellings visible at high magnification under the light microscope. Such axonal swellings coincide with synaptic boutons, as has been demonstrated in a number of combined light and electron microscopic studies. These studies also indicated that, in most cases, one bouton corresponds precisely to one synapse. Golgi-impregnated axonal trees of 20 neocortical pyramidal neurons were drawn with a camera lucida. Axonal swellings were marked on the drawings. Most swellings were 'en passant'; occasionally, they were situated at the tip of short, spine-like processes. On axon collaterals, the average interval between swellings was 4.5 microns. On the axonal main stem, the swellings were always less densely packed than on the collaterals. Statistical analysis of the spatial distribution of the swellings did not reveal any special patterns. Instead, the arrangement of swellings on individual collaterals follows a Poisson distribution. Moreover, the same holds to a large extent for the entire collection of pyramidal cell collaterals. This suggests that a single Poisson process, characterized by only one rate parameter (number of synapses per unit length), describes most of the spatial distribution of synapses along pyramidal cell collaterals. These findings do not speak in favour of a pronounced target specificity of pyramidal neurons at the synaptic level. Instead, our results support a probabilistic model of cortical connectivity.

Animals↗
PubMed1983

A practical approach to the hepatobiliary kinetics of 99mTc-HIDA. Clinical validation of the method and a preliminary report on its use for parametric imaging.

99mTc-diethyl-HIDA cholescintigraphy was performed on 24 patients with histologically proven liver disease and on 10 normal adult subjects. Liver mass transport of HIDA was interpreted with the aid of a probabilistic model, assuming that the tracer particles undergo mixed random walks with drifts. The radiohepatograms were thus fitted with a gamma-variate function and the fitting parameters were evaluated as estimates of the severity of the disease. These parameters, together with the transit times, were also used to generate parametric images of liver function. The advantages of this approach are discussed and the following conclusions are drawn: (1) The gamma-fit is highly satisfactory with any type of experimental curve (0.98 less than r less than 1). (2) The parameters derived from the gamma-fit make it possible to objectively assess the extent of liver functional impairment. (3) Parametric imaging of the liver mass transport of HIDA is easily implemented, but still more experience is needed to assess its impact on patient care.

Bile Ducts↗
PubMed1993

In vivo validation of distributed source solutions for the biomagnetic inverse problem.

Probabilistic modelling of continuous current sources is applied to the analysis of MEG signals generated by current dipoles implanted in the head of a living human subject. Estimates of the distribution of activity within a circular disk are obtained from signals generated by a single implanted dipole and by a pair of simultaneously active implanted dipoles. The orientation and depth of the disc is determined in advance from the experimental geometry and the measurements. The resulting reconstructions constitute the first in vivo validation of distributed source imaging; they provide a complementary test to earlier works using computer generated data and tests using point source analysis of signals generated by a single implanted dipole. In this work we provide a literal test of spatial resolution by resolving two nearby point-like sources. Temporal resolution is addressed in a de facto manner by imaging at one millisecond intervals. Computer simulations, with controlled amount of noise, are used to demonstrate the robustness of the results, and show the interplay between high spatial accuracy and noise insensitivity.

Brain↗
PubMed1991

Experiments on the seasonality of the cesium translocation in cereals, potatoes and vegetables.

The translocation of cesium from leaves into the edible parts after foliar deposition at different stages of growth has been determined for cereals, potatoes, green beans and carrots in field experiments. For all the plant species investigated a significant seasonality of the cesium translocation was observed. The highest translocation factors were determined after foliar contamination 50 to 60 days before harvest for cereals, and 70 to 90 days and 15 days before harvest for potatoes and green beans, respectively. The variations among the different experiments can be reduced when the translocation is normalized to the yield. This facilitates the application in probabilistic models due to the implicit consideration of the relationship between translocation and yield. The seasonality of the cesium translocation can be described with gaussian functions being consistent with the physiological development of cereals and potatoes. The uncertainty of these approaches is a factor of 3 and 4 for cereals and potatoes, respectively.

Biological Transport↗
PubMed1996

Predicting axillary lymph node metastases in breast carcinoma patients.

Routine axillary dissection is primarily used as a means of assessing prognosis to establish appropriate treatment plans for patients with primary breast carcinoma. However, axillary dissection offers no therapeutic benefit to node negative patients and patients may incur unnecessary morbidity, including mild to severe impairment of arm motion and lymphedema, as a result. This paper outlines a method of evaluating the probability of harbouring lymph node metastases at the time of initial surgery by assessment of tumour based parameters, in order to provide an objective basis for further selection of patients for treatment or investigation. The novel aspect of this study is the use of Maximum Entropy Estimation (MEE) to construct probabilistic models of the relationship between the risk factors and the outcome. Two hundred and seventeen patients with invasive breast carcinoma were studied. Surgical treatment included axillary clearance in all cases, so that the pathologic status of the nodes was known. Tumour size was found to be significantly correlated (P < 0.001) to the axillary lymph node status in the multivariate anlaysis with age (P = 0.089) and vascular invasion (P = 0.08) marginally correlated. Using the multivariate model constructed, 38 patients were predicted to have risk of nodal metastases lower than 20%, of these only 4 (10%) patients had lymph node metastases. A comparison with the Multivariate Logistic Regression (MLR) was carried out. It was found that the predictive quality of the MEE model was better than that of the MLR model. In view of the small sample size, further verification of this model is required in assessing its practical application to a larger population.

Axilla↗
PubMed2004

Stability and change in perception: spatial organization in temporal context.

Perceptual multistability has often been explained using the concepts of adaptation and hysteresis. In this paper we show that effects that would typically be accounted for by adaptation and hysteresis can be explained without assuming the existence of dedicated mechanisms for adaptation and hysteresis. Instead, our data suggest that perceptual multistability reveals lasting states of the visual system rather than changes in the system caused by stimulation. We presented observers with two successive multistable stimuli and found that the probability that they saw the favored organization in the first stimulus was inversely related to the probability that they saw the same organization in the second. This pattern of negative contingency is orientation-tuned and occurs no matter whether the observer had or had not seen the favored organization in the first stimulus. This adaptation-like effect of negative contingency combines multiplicatively with a hysteresis-like effect that increases the likelihood of the just-perceived organization. Both effects are consistent with a probabilistic model in which perception depends on an orientation-tuned intrinsic bias that slowly (and stochastically) changes its orientation tuning over time.

Adaptation, Physiological↗
PubMed2003

Assessment of PCB congener analytical methods: do they meet risk assessment needs?

Congener-specific PCB analysis allows use of toxic equivalency (TEQ) TCDD-based risk assessment approaches when analytical methods are sufficiently sensitive. Many efforts to analyze fish samples for PCB congeners report the majority of samples as non-detects; these data are of little use for human health risk assessment if the limits of analytical detection exceed levels of potential health concern. However, increasing analytical sensitivity is costly and technically difficult. An approach to assess analytical sensitivity needs for risk assessment by defining toxicological endpoints of concern and acceptable risk levels is presented. This framework was applied to assessment of potential PCB TEQ cancer risks to the general United States population and tribal consumers of Columbia River fish, but may be easily adjusted for other situations. A probabilistic model was used to calculate the necessary analytical sensitivity for PCB TEQ cancer risk assessment using the Environmental Protection Agency's new draft cancer risk slope factor for TCDD and fish consumption data. Desired levels of analytical sensitivity were estimated for the congener expected to contribute the most to PCB TEQ, PCB 126, and compared to limits of detection for various analytical methods. The financial and health value of methods with different levels of analytical sensitivity were compared using a value of information approach, which includes analytical cost and cost of potential health outcomes, and a proposed risk assessment utility approach which considers the relative health protectiveness of analytical options non-monetarily. Sensitivity analyses indicate that average consumption rate, cancer risk slope factor choice, and knowledge of existing PCB contamination are important considerations for planning PCB congener analysis.

Animals↗
PubMedDate not supplied

Reducing the occupational risk of infections for the surgeon: multicentric national survey on more than 15,000 surgical procedures.

The objective of this study was to find the incidence of accidental exposures to blood and body fluids among surgeons during operations and to describe their dynamics. A probabilistic model was also used to predict the cumulative 30-year risk to the surgeon of contracting hepatitis B and C viruses (HBV, HCV) or human immunodeficiency virus (HIV) infection and estimate the effect of preventive strategies in reducing this risk. A multicentric prospective survey, based on self-administered questionnaires, was conducted during a period of 6 months in 39 Italian hospitals. As accidental exposure to blood or body fluids occurred in 9.2% of 15,375 operations. In about 2% of procedures a parenteral-type injury, such as actual skin puncture or eye contamination, was suffered by the operating surgeon. A needle-stick injury was the commonest accident, and its occurrence was found to vary with the phase of the procedure and its length. The current lifetime risk of acquiring HBV, HCV, and HIV infection in our regions was estimated to be as high as 42.7%, 34.8%, and 0.54%, respectively. The adoption of preventive strategies is expected to reduce this risk to 21% for HBV, 16.6% for HCV, and 0.23% for HIV infection. Active immunization of surgeons against HBV is strongly recommended. The case is also made for the use of a face-shield combined with a permanent change in our surgical practice capable of reducing the current high rate of parenteral injuries.

General Surgery↗
PubMed2000

Random binding of dimers to chains.

We develop a probabilistic model for the binding of a small linear polymer to a larger chain. We assume that we can approximate the energy of interaction of the two chains by summing the pairwise interactions between subunits. Because the energy of interaction between a pair of subunits can depend on neighboring subunits, which we assume vary along the chain, we assign the pairwise energies of interactions according to a specified probability distribution. Thus we develop a statistical model for the binding of two molecules. While such models may not be appropriate for studying the interaction of a particular pair of molecules, they can provide insight into questions that deal with populations of molecules, such as why do MHC molecules bind peptides of a certain size? Here we analyze in detail the special case of a heterodimer binding to a polymer.

HLA Antigens↗
PubMed2005

Human archival tissues provide a valuable source for the analysis of spatial genome organization.

Sections from archival formalin-fixed, paraffin wax-embedded human tissues are a valuable source for the study of the nuclear architecture of specific tissue types in terms of the three-dimensional spatial positioning and architecture of chromosome territories and sub-chromosomal domains. Chromosome painting, centromeric, and locus-specific probes were hybridized to tissue microarrays prepared from formalin-fixed paraffin wax-embedded samples of pancreas and breast. The cell nuclei were analyzed using quantitative three-dimensional image microscopy. The results obtained from non-neoplastic pancreatic cells of randomly selected individuals indicated that the radial arrangement of the chromosome 8 territories as well as their shape (roundness) did not significantly differ between the individuals and were in accordance with assumptions of a probabilistic model for computer simulations. There were considerable differences between pancreatic tumor and non-neoplastic cells. In non-neoplastic ductal epithelium of the breast there was a larger, but insignificant, variability in the three-dimensional positioning of the centromere 17 and HER2 domains between individuals. In neoplastic epithelial breast cells, however, the distances between centromere and gene domains were, on average, smaller than in non-neoplastic cells. In conclusion, our results demonstrate the feasibility of studying the genome architecture in archival, formalin-fixed, paraffin wax-embedded human tissues, opening new directions in tumor research and cell classification.

Breast↗
PubMed2004

Reasoning of spike glycoproteins being more vulnerable to mutations among 158 coronavirus proteins from different species.

In this study, we used the probabilistic models developed by us over the last several years to analyze 158 proteins from coronaviruses in order to determine which protein is more vulnerable to mutations. The results provide three lines of evidence suggesting that the spike glycoprotein is different from the other coronavirus proteins: (1) the spike glycoprotein is more sensitive to mutations, this is the current state of the spike glycoprotein, (2) the spike glycoprotein has undergone more mutations in the past, this is the history of spike glycoprotein, and (3) the spike glycoprotein has a bigger potential towards future mutations, this is the future of spike glycoprotein. Furthermore, this study gives a clue on the species susceptibility regarding different proteins.

Analysis of Variance↗