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A study of the organization of light- and heavy-chain immunoglobulin genes in mouse splenic B cells, spleen-derived hybridomas and plasmacytomas has unequivocally demonstrated that aberrant rearrangements are common during normal B-cell development. The results support a probabilistic model for allelic exclusion of immunoglobulin gene expression.
Experimental evidence is presented indicating that the expression of a lacZ reporter gene driven by the HIV-1 long terminal repeat in a series of stably transfected, cloned macrophage cell lines occurs in a very small proportion of cells. The proportion of cells expressing lacZ, rather than the level of expression in each cell, is regulated by external stimuli such as LPS and phorbol ester. Based upon these and published data we propose that transcription in eukaryotic cells occurs in short pulses interspersed by long periods of inactivity of indeterminate duration. Transcriptional regulation is envisaged as involving changes in the probability rather than the rate of transcription. A probabilistic model of transcription may explain many biological phenomena, such as stem cell division and clonogenic activity, heterogeneous gene expression among clonal cell populations, retroviral latency and cell cycle progression, which appear to involve stochastic decisions.
When we learn a new motor skill, such as playing an approaching tennis ball, both our sensors and the task possess variability. Our sensors provide imperfect information about the ball's velocity, so we can only estimate it. Combining information from multiple modalities can reduce the error in this estimate. On a longer time scale, not all velocities are a priori equally probable, and over the course of a match there will be a probability distribution of velocities. According to bayesian theory, an optimal estimate results from combining information about the distribution of velocities-the prior-with evidence from sensory feedback. As uncertainty increases, when playing in fog or at dusk, the system should increasingly rely on prior knowledge. To use a bayesian strategy, the brain would need to represent the prior distribution and the level of uncertainty in the sensory feedback. Here we control the statistical variations of a new sensorimotor task and manipulate the uncertainty of the sensory feedback. We show that subjects internally represent both the statistical distribution of the task and their sensory uncertainty, combining them in a manner consistent with a performance-optimizing bayesian process. The central nervous system therefore employs probabilistic models during sensorimotor learning.
Genetic interaction analysis,in which two mutations have a combined effect not exhibited by either mutation alone, is a powerful and widespread tool for establishing functional linkages between genes. In the yeast Saccharomyces cerevisiae, ongoing screens have generated >4,800 such genetic interaction data. We demonstrate that by combining these data with information on protein-protein, prote in-DNA or metabolic networks, it is possible to uncover physical mechanisms behind many of the observed genetic effects. Using a probabilistic model, we found that 1,922 genetic interactions are significantly associated with either between- or within-pathway explanations encoded in the physical networks, covering approximately 40% of known genetic interactions. These models predict new functions for 343 proteins and suggest that between-pathway explanations are better than within-pathway explanations at interpreting genetic interactions identified in systematic screens. This study provides a road map for how genetic and physical interactions can be integrated to reveal pathway organization and function.
Transcriptional activation is often associated with chromatin remodeling. However, little is known about the dynamics of remodeling of nucleosome arrays in vivo. Upon induction of Saccharomyces cerevisiae PHO5, a novel kinetic assay of DNA methyltransferase accessibility showed that nucleosomes adjacent to the histone-free upstream activating sequence (UASp1) are disrupted earlier and at higher frequency in the cell population than are those more distal. Individually cloned molecules, each representing the chromatin state of a full promoter from a single cell, revealed multiple promoter classes with either no remodeling or variable numbers of disrupted nucleosomes. Individual promoters in the remodeled fraction were highly enriched for contiguous blocks of disrupted nucleosomes, the majority of which overlapped the UAS region. These results support a probabilistic model in which chromatin remodeling at PHO5 spreads from sites of transactivator association with DNA and attenuates with distance.
The immune system comprises multiple cell lineages and subsets maintained in tissues throughout the lifespan, with unknown effects of tissue and age on immune cell function. Here we comprehensively profiled RNA and surface protein expression of over 1.25 million immune cells from blood and lymphoid and mucosal tissues from 24 organ donors aged 20-75 years. We annotated major lineages (T cells, B cells, innate lymphoid cells and myeloid cells) and corresponding subsets using a multimodal classifier and probabilistic modeling for comparison across tissue sites and age. We identified dominant site-specific effects on immune cell composition and function across lineages; age-associated effects were manifested by site and lineage for macrophages in mucosal sites, B cells in lymphoid organs, and circulating T cells and natural killer cells across blood and tissues. Our results reveal tissue-specific signatures of immune homeostasis throughout the body, from which to define immune pathologies across the human lifespan.
The issue of whether multiple, ipsilateral or bilateral, breast carcinomas represent multiple primary tumours or dissemination of a single carcinomatous process has been difficult to resolve, especially for individual patients. We have addressed the problem by comparative genomic hybridisation analysis of 26 tumours from 12 breast cancer patients with multiple ipsilateral and/or bilateral carcinoma lesions. Genomic imbalances were detected in 25 of the 26 (96%) tumours. Using the genomic imbalances detected in these 26 lesions as well as those previously found by us in an independent series of 35 unifocal breast carcinomas, we compared a probabilistic model for likelihood of independence with unsupervised hierarchical clustering methodologies to determine the clonal relatedness of multiple tumours in breast cancer patients. We conclude that CGH analysis of multiple breast carcinomas followed by unsupervised hierarchical clustering of the genomic imbalances is more reliable than previous criteria to determine the tumours' clonal relationship in individual patients, that most ipsilateral breast carcinomas arise through intramammary spreading of a single breast cancer, and that most patients with bilateral breast carcinomas have two different diseases.
The relationships among pairwise judgments of the quality of connected discourse, pairwise judgments of the relative intelligibility of discourse, and measured intelligibility on a nonsense-syllable test were evaluated under identical conditions of primary talker and competitive babble. Stimuli were processed by eight hearing aids and presented in a repeated-measures design to 12 listeners with sensorineural hearing loss. Results revealed moderately high test-retest reliability for all three experimental conditions. Overall, a noteworthy positive relationship was evident between relative intelligibility judgments and measured phonemic identification, although this relationship varied considerably among individual listeners. The correspondence between quality judgments and relative intelligibility judgments was substantially lower, while the relationship between judgments of quality and phonemic identification scores was negligible. Findings demonstrate the potential importance of instructional set in producing valid judgments of the relative intelligibility of aided speech. The determination of measurement error inherent in pairwise preference data is discussed from the viewpoint of a probabilistic model encompassing a binomial distribution. It is concluded that experimental optimization of the agreement between relative intelligibility judgments and measured intelligibility performance of individual listeners will be required before the pairwise comparison technique can be considered a viable alternative to traditional hearing aid evaluation procedures.
In order to estimate the public health impact of helminth infections, and to provide baseline data for interventions, parasitological and morbidity surveys were conducted among inhabitants of three villages in Dongting Lake region, Hunan Province, China. Ascaris lumbricoides was found to be the most common helminth infection, followed by Trichuris trichiura and Schistosoma japonicum. Left liver enlargement was the most common indicator of morbidity. Observed numbers of multiple species infections closely correlated with expected figures generated from a simple probabilistic model. Heterogeneity was observed in age and sex-standardized infection and morbidity prevalences among the villages and occupations. Males had higher levels of infection, were more likely to suffer morbidity, and were more likely to have been treated for schistosomiasis than women. The prevalence of each morbidity indicator was positively correlated with the number of times of treatment for schistosomiasis, and negatively correlated with number of years since last treatment. The results imply that treatment history for S. japonicum infection may be a good indicator of current morbidity risk.
Mature T and B lymphocytes respond to receptor-delivered signals received during and following activation. These signals regulate the rates of cell death, growth, differentiation and migration that ultimately establish the behaviour patterns collectively referred to as immune regulation. We have been pursuing the philosophy that in vitro systems of lymphocyte stimulation, when analysed quantitatively, help reveal the logical attributes of lymphocyte behaviour. The development of carboxyfluorescein diacetate succinimidyl ester (CFSE) to track division has enabled the variable of division number to be incorporated into these quantitative analyses. Our studies with CFSE have established a fundamental link between differentiation and division number. Isotype switching, expression of T cell cytokines, surface receptor alterations and changes to intracellular signalling components all display independent patterns of change with division number. The stochastic aspects of these changes and the ability of external signals to independently regulate them argue for a probabilistic modelling framework for describing and understanding immune regulation.
BACKGROUND & AIMS: In previous studies about the natural history of chronic hepatitis C (CHC), age at the time of infection correlated with the rate at which hepatic fibrosis progresses. The presence of a competing risk, namely higher mortality from natural causes, may contribute to this observation. A simulation experiment was conducted to measure the magnitude of the effect of competing risks on the observed rate of fibrosis progression of CHC. METHODS: A computer-based probabilistic model was created in which fibrosis of CHC progressed from stage 0 to 4 (cirrhosis) in 20-year-old and 50-year-old male and female cohorts. The rate of fibrosis progression was randomly assigned to each simulated individual from a distribution common to all age- and sex-specific cohorts. The cohorts also experienced mortality from natural causes according to the 2000 census data. RESULTS: The observed median time to reach cirrhosis for the 50-year-old cohorts was 20.4 +/- 0.2 years compared with 29.7 +/- 0.2 for the 20-year-old cohorts ( P < 0.01). The median time to reach cirrhosis in men was 24.2 +/- 0.6 years compared with 25.9 +/- 0.6 in women ( P = 0.01). Overall, the observed rate of progression was slowest among young women. Similarly, accelerating mortality from natural causes, simulating the impact of comorbid conditions that shorten survival, reduced the observed time to reach cirrhosis. CONCLUSIONS: Even if the underlying rate of fibrosis progression in CHC was held constant, the time to reach cirrhosis will be observed to be substantially shorter in subjects with a higher competing mortality.
An important factor in judging whether two retinal images arise from the same object viewed from different positions may be the presence of certain properties or cues that are 'qualitative invariants' with respect to the natural transformations, particularly affine transformations, associated with changes in viewpoint. To test whether observers use certain affine qualitative cues such as concavity, convexity, collinearity, and parallelism of the image elements, a 'same-different' discrimination experiment was carried out with planar patterns that were defined by four points either connected by straight line segments (line patterns) or marked by dots (dot patterns). The first three points of each pattern were generated randomly; the fourth point fell on their diagonal bisector. According to the position of that point, the patterns were concave, triangular (three points being collinear), convex, or parallel sided. In a 'same' trial, an affine transformation was applied to one of two identical patterns; in a 'different' trial, the affine transformation was applied after the point lying on the diagonal bisector was perturbed a short, fixed distance along the bisector, inwards for one pattern and outwards for the other. Observers' ability to discriminate 'same' from 'different' pairs of patterns depended strongly on the position of the fourth, displaced, point: performance varied rapidly when the position of the displaced point was such that the patterns were nearly triangular or nearly parallel sided, consistent with observers using the hypothesised qualitative cues. The experimental data were fitted with a simple probabilistic model of discrimination performance that used a combination of these qualitative cues and a single quantitative cue.
The integration of information from different sensors, cues, or modalities lies at the very heart of perception. We are studying adaptive phenomena in visual cue integration. To this end, we have designed a visual tracking task, where subjects track a target object among distractors and try to identify the target after an occlusion. Objects are defined by three different attributes (color, shape, size) which change randomly within a single trial. When the attributes differ in their reliability (two change frequently, one is stable), our results show that subjects dynamically adapt their processing. The results are consistent with the hypothesis that subjects rapidly re-weight the information provided by the different cues by emphasizing the information from the stable cue. This effect seems to be automatic, ie not requiring subjects' awareness of the differential reliabilities of the cues. The hypothesized re-weighting seems to take place in about 1 s. Our results suggest that cue integration can exhibit adaptive phenomena on a very fast time scale. We propose a probabilistic model with temporal dynamics that accounts for the observed effect.
The rapid worldwide spread of severe acute respiratory syndrome demonstrated the potential threat an infectious disease poses in a closely interconnected and interdependent world. Here we introduce a probabilistic model that describes the worldwide spread of infectious diseases and demonstrate that a forecast of the geographical spread of epidemics is indeed possible. This model combines a stochastic local infection dynamics among individuals with stochastic transport in a worldwide network, taking into account national and international civil aviation traffic. Our simulations of the severe acute respiratory syndrome outbreak are in surprisingly good agreement with published case reports. We show that the high degree of predictability is caused by the strong heterogeneity of the network. Our model can be used to predict the worldwide spread of future infectious diseases and to identify endangered regions in advance. The performance of different control strategies is analyzed, and our simulations show that a quick and focused reaction is essential to inhibiting the global spread of epidemics.
With the help of simple probabilistic models of Kac and McKean, we discuss the meaning of the generalized expression for entropy that was recently introduced by our group and compare it with Boltzmann's expression. We emphasize the fact that Boltzmann's formulation in terms of the single particle distribution function, f(1), requires very restricted assumptions about the preparation of the system (chaos) and the nature of the collision mechanism (Markov processes).Our generalized [unk]-theorem, however, refers to the complete system; in general, it does not lead to an [unk]-theorem for the single particle distribution function, f(1). It is valid whatever the preparation of the system. In McKean's model, situations exist where it gives the correct behavior while the Boltzmann's expression for entropy becomes meaningless. In addition, in Kac's model, we show that correlations reach equilibrium more rapidly than f(1) and that there is an asymptotic regime where both formulations give the same result.
We have used Southern's blotting technique to determine the extent to which the genes encoding the constant (C) regions of mu, alpha, gamma(1), and gamma(2b) immunoglobulin heavy (H) chains are altered in number and context from their germline (embryo) state in a series of 14 plasmacytomas expressing various H chain classes. In the three mu chain-producing plasmacytomas studied there was no evidence of rearrangement of C(H) genes other than C(mu). In contrast, rearrangement and deletion of nonexpressed C(H) genes was frequent in plasmacytomas that produce gamma or alpha chains. The observed pattern of deletions is consistent with the idea that the ontogenetic switch in H chain class requires C(H) gene deletion. Frequently, though not always, such deletions as well as other types of rearrangement occur in both allelic loci. Particularly noteworthy are three gamma(2a)-expressing tumors in which C(alpha) gene rearrangement is evident in both alleles. We incorporate these observations into a probabilistic model of B cell development: in the first phase, deletions may occur between the C(mu) gene and the variable (V(H)) gene array, which result in the formation of a productive fused V(H)-C(mu) gene. The cell may then enter a second phase, which allows deletions within the C(H) gene arrays of both homologous chromosomes. Some deletions juxtapose the expressed V(H) gene with a second C(H) gene and result in a H chain class switch; others delete or alter the context of C(H) genes without changing the phenotype of the cell. We predict that switching can be both a single-step and a multi-step process, and that in the latter case those rearrangements that do not result in a switch may be physiologically significant in that they may limit the options of further switching.
The pivotal process in gene-culture coevolution is envisaged to be the evolution of behavioral epigenesis. From premises based on the known properties of enculturation and usage diffusion within societies, a probabilistic model is constructed to estimate the degree to which rules governing individual development canalize ethnographic curves (the probability density distributions of societies engaged in varying patterns of usage). The results indicate that under most conceivable conditions the translation from individual epigenesis to social pattern is amplified, to an extent that differences in bias too faint to be detected in ordinary developmental studies can generate conspicuous variation in the ethnographic curves. Examples are cited of sufficiently biased epigenesis in human behavior.
Whether or not nuclear introns predate the divergence of bacteria and eukaryotes is the central argument between the proponents of the "introns-early" and "introns-late" theories. In this study we compared the goodness-of-fit of each theory with a probabilistic model of exon/intron evolution and multiple nonallelic genes encoding human aldehyde dehydrogenases (ALDHs). Using a reconstructed phylogenetic tree of ALDH genes, we computed the likelihood of obtaining the present-day ALDH sequences under the assumptions of each competing theory. Although on the grounds of its own assumptions each theory accounted for the ALDH data significantly better than its rival, the introns-early model required frequent intron slippage, and the estimated slippage rates were too high to be consistent with reported correlations between the boundaries of ancient protein modules and the ends of ancient exons. Because the molecular mechanisms proposed to explain intron slippage are incapable of providing such high rates and are incompatible with the observed distribution of introns in higher eukaryotes, the ALDH data support the introns-late theory.