Showing papers by "James J. Collins published in 2003"

Noise in eukaryotic gene expression

Abstract: Transcription in eukaryotic cells has been described as quantal, with pulses of messenger RNA produced in a probabilistic manner. This description reflects the inherently stochastic nature of gene expression, known to be a major factor in the heterogeneous response of individual cells within a clonal population to an inducing stimulus. Here we show in Saccharomyces cerevisiae that stochasticity (noise) arising from transcription contributes significantly to the level of heterogeneity within a eukaryotic clonal population, in contrast to observations in prokaryotes, and that such noise can be modulated at the translational level. We use a stochastic model of transcription initiation specific to eukaryotes to show that pulsatile mRNA production, through reinitiation, is crucial for the dependence of noise on transcriptional efficiency, highlighting a key difference between eukaryotic and prokaryotic sources of noise. Furthermore, we explore the propagation of noise in a gene cascade network and demonstrate experimentally that increased noise in the transcription of a regulatory protein leads to increased cell-cell variability in the target gene output, resulting in prolonged bistable expression states. This result has implications for the role of noise in phenotypic variation and cellular differentiation.

Inferring genetic networks and identifying compound mode of action via expression profiling

Abstract: The complexity of cellular gene, protein, and metabolite networks can hinder attempts to elucidate their structure and function. To address this problem, we used systematic transcriptional perturbations to construct a first-order model of regulatory interactions in a nine-gene subnetwork of the SOS pathway in Escherichia coli. The model correctly identified the major regulatory genes and the transcriptional targets of mitomycin C activity in the subnetwork. This approach, which is experimentally and computationally scalable, provides a framework for elucidating the functional properties of genetic networks and identifying molecular targets of pharmacological compounds.

Prediction and measurement of an autoregulatory genetic module

Abstract: The deduction of phenotypic cellular responses from the structure and behavior of complex gene regulatory networks is one of the defining challenges of systems biology This goal will require a quantitative understanding of the modular components that constitute such networks We pursued an integrated approach, combining theory and experiment, to analyze and describe the dynamics of an isolated genetic module, an in vivo autoregulatory gene network As predicted by the model, temperature-induced protein destabilization led to the existence of two expression states, thus elucidating the trademark bistability of the positive feedback-network architecture After sweeping the temperature, observed population distributions and coefficients of variation were in quantitative agreement with those predicted by a stochastic version of the model Because model fluctuations originated from small molecule-number effects, the experimental validation underscores the importance of internal noise in gene expression This work demonstrates that isolated gene networks, coupled with proper quantitative descriptions, can elucidate key properties of functional genetic modules Such an approach could lead to the modular dissection of naturally occurring gene regulatory networks, the deduction of cellular processes such as differentiation, and the development of engineered cellular control

Reverse engineering gene networks: Integrating genetic perturbations with dynamical modeling

Abstract: While the fundamental building blocks of biology are being tabulated by the various genome projects, microarray technology is setting the stage for the task of deducing the connectivity of large-scale gene networks. We show how the perturbation of carefully chosen genes in a microarray experiment can be used in conjunction with a reverse engineering algorithm to reveal the architecture of an underlying gene regulatory network. Our iterative scheme identifies the network topology by analyzing the steady-state changes in gene expression resulting from the systematic perturbation of a particular node in the network. We highlight the validity of our reverse engineering approach through the successful deduction of the topology of a linear in numero gene network and a recently reported model for the segmentation polarity network in Drosophila melanogaster. Our method may prove useful in identifying and validating specific drug targets and in deconvolving the effects of chemical compounds.

Literacy and Literacies: Texts, Power, and Identity

Abstract: Literacy and Literacies is an engaging account of literacy and its relation to power. The book develops a synthesis of literacy studies, moving beyond received categories, and exploring the domain of power through questions of colonialism, modern state formation, educational systems and official versus popular literacies. Collins and Blot offer in-depth critical discussion of particular cases and discuss the role of literacies in the formation of class, gender, and ethnic identity. Through their analysis of two domains - those of literacies and power, and of literacies and subjectivity - they challenge received assumptions about literacy, intellectual development and social progress and argue that neither 'universalist' nor 'particularist' accounts offer satisfactory approaches to the phenomenon. This is a sustained exploration of the domain of power in relation to literacy. It will be welcomed by students and researchers in anthropology, linguistics, literacy studies and history.

Reduction in injury rates in nursing personnel through introduction of mechanical lifts in the workplace

Abstract: BACKGROUND: Health care workers incur frequent injuries resulting from patient transfer and handling tasks. Few studies have evaluated the effectiveness of mechanical lifts in preventing injuries and time loss due to these injuries. METHODS: We examined injury and lost workday rates before and after the introduction of mechanical lifts in acute care hospitals and long-term care (LTC) facilities, and surveyed workers regarding lift use. RESULTS: The post-intervention period showed decreased rates of musculoskeletal injuries (RR = 0.82, 95% CI: 0.68-1.00), lost workday injuries (RR = 0.56, 95% CI: 0.41-0.78), and total lost days due to injury (RR = 0.42). Larger reductions were seen in LTC facilities than in hospitals. Self-reported frequency of lift use by registered nurses and by nursing aides were higher in the LTC facilities than in acute care hospitals. Observed reductions in injury and lost day injury rates were greater on nursing units that reported greater use of the lifts. CONCLUSIONS: Implementation of patient lifts can be effective in reducing occupational musculoskeletal injuries to nursing personnel in both LTC and acute care settings. Strategies to facilitate greater use of mechanical lifting devices should be explored, as further reductions in injuries may be possible with increased use. Language: en

The engineering of gene regulatory networks.

Abstract: The rapid accumulation of genetic information and advancement of experimental techniques have opened a new frontier in biomedical engineering. With the availability of well-characterized components from natural gene networks, the stage has been set for the engineering of artificial gene regulatory networks with sophisticated computational and functional capabilities. In these efforts, the ability to construct, analyze, and interpret qualitative and quantitative models is becoming increasingly important. In this review, we consider the current state of gene network engineering from a combined experimental and modeling perspective. We discuss how networks with increased complexity are being constructed from simple modular components and how quantitative deterministic and stochastic modeling of these modules may provide the foundation for accurate in silico representations of gene regulatory network function in vivo.

Noise-enhanced human sensorimotor function

Abstract: We review our work on using input noise (mechanical and electrical, respectively) to enhance somatosensation in humans and improve the performance of the human balance control system. We also discuss bioengineering applications and future directions for stochastic resonance (SR) based techniques and devices. Age- and disease-related sensory loss may be reversible by exploiting SR-type effects.

Lymphohaematopoeitic cancer mortality among workers with benzene exposure

Abstract: Lymphohaematopoeitic cancer mortality was examined among 4417 workers at a chemical plant by cumulative and peak benzene exposure There was little evidence of increasing risk with increasing cumulative exposure for all leukaemias or acute non-lymphocytic leukaemias (ANL), or the other lymphohaematopoeitic cancers with the exception of multiple myeloma For multiple myeloma, the SMRs were 11 (95% CI 03 to 25) in the non-exposed group, 14 (95% CI 02 to 51) in the 6 ppm-years group We found no trends by peak exposures for any of the cancers However, when peak exposures over 100 ppm for 40 or more days were considered, the observed number of all leukaemias (SMR = 27, 95% CI 08 to 64), ANL (SMR = 41, 95% CI 05 to 149), and multiple myeloma (SMR = 40, 95% CI 08 to 117) were greater than expected While the observed number of deaths is small in this study, the number of peak exposures greater than 100 ppm to benzene is a better predictor of risk than cumulative exposure The dose rate of benzene and a threshold for exposure response may be important factors for evaluating lymphohaematopoietic risk

Robust identification of large genetic networks.

Abstract: Temporal and spatial gene expression, together with the concentration of proteins and metabolites, is tightly controlled in the cell. This is possible thanks to complex regulatory networks between these different elements. The identification of these networks would be extremely valuable. We developed a novel algorithm to identify a large genetic network, as a set of linear differential equations, starting from measurements of gene expression at steady state following transcriptional perturbations. Experimentally, it is possible to overexpress each of the genes in the network using an episomal expression plasmid and measure the change in mRNA concentration of all the genes, following the perturbation. Computationally, we reduced the identification problem to a multiple linear regression, assuming that the network is sparse. We implemented a heuristic search method in order to apply the algorithm to large networks. The algorithm can correctly identify the network, even in the presence of large noise in the data, and can be used to predict the genes that directly mediate the action of a compound. Our novel approach is experimentally feasible and it is readily applicable to large genetic networks.

Method and apparatus for neurophysiologic performance

Abstract: The invention features methods and apparatus for enhancing neurophysiologic performance, such as sensorimotor control and neuroplasticity. A preferred method involves inputting bias signals to sensory cells of a subject, thereby improving sensory cell function, while the subject is performing a predefined physical activity. A system used to practice the method of the invention includes a wearable device to which is secured at least one repositionable signal input device and a signal generator that is communicatively coupled to the signal input devices.

Cancer risk for chemical workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

Abstract: Aims: To describe the long term mortality experience of a cohort of 2187 male chemical production workers previously exposed to substantial levels of dioxin. Methods: Vital status for a previously identified cohort was determined for an additional 10 years, to 1995. Dioxin exposures took place before 1983 and were sufficient to result in chloracne in 245 individuals. Mortality rates were compared with national figures and with a large pool of co-workers in unrelated production jobs. Results: All cancers combined (standardised mortality ratio (SMR) = 1.0, 95% CI 0.8 to 1.1) and lung cancer (SMR = 0.8, 95% CI 0.6 to 1.1) were at or below expected levels. Rates for soft tissue sarcoma (SMR = 2.4, 95% CI 0.3 to 8.6) and non-Hodgkin’s lymphoma (SMR = 1.4, 95% CI 0.6 to 2.7) were greater than expected overall, but below expectation in the update period. No trend of increasing risk with increasing exposure was observed for these cancers. Workers who developed chloracne had very low all-cancer rates (SMR = 0.5, 95% CI 0.3 to 1.0), and lung cancer rates (SMR = 0.3, 95% CI 0.0 to 1.1). Conclusions: We found no coherent evidence of increased cancer risk from dioxin exposure in this cohort. Our study highlights the wide range of cancer rates and the lack of consistency across dioxin studies.

Cis/trans riboregulators

Abstract: The present invention provides nucleic acid molecules, DNA constructs, plasmids, and methods for post-transcriptional regulation of gene expression using RNA molecules to both repress and activate translation of an open reading frame. Repression of gene expression is achieved through the presence of a regulatory nucleic acid element (the cis-repressive RNA or crRNA) within the 5' untranslated region (5' UTR) of an mRNA molecule. The nucleic acid element forms a hairpin (stem/loop) structure through complementary base pairing. The hairpin blocks access to the mRNA transcript by the ribosome, thereby preventing translation. In particular, in embodiments of the invention designed to operate in prokaryotic cells, the stem of the hairpin secondary structure sequesters the ribosome binding site (RBS). In embodiments of the invention designed to operate in eukaryotic cells, the stem of the hairpin is positioned upstream of the start codon, anywhere within the 5' UTR of an mRNA. A small RNA (trans-activating RNA, or taRNA), expressed in trans, interacts with the crRNA and alters the hairpin structure. This alteration allows the ribosome to gain access to the region of the transcript upstream of the start codon, thereby activating transcription from its previously repressed state.

The effects of stochastic monopolar galvanic vestibular stimulation on human postural sway.

Abstract: Galvanic vestibular stimulation (GVS) is a technique in which small currents are delivered transcutaneously to the afferent nerve endings of the vestibular system through electrodes placed over the mastoid bones. The applied current alters the firing rates of the peripheral vestibular afferents, causing a shift in a standing subject's vestibular perception and a corresponding postural sway. Previously, we showed that in subjects who are facing forward, stochastic bipolar binaural GVS leads to coherent stochastic mediolateral postural sway. The goal of this pilot study was to extend that work and to test the hypothesis that in subjects who are facing forward, stochastic monopolar binaural GVS leads to coherent stochastic anteroposterior postural sway. Stochastic monopolar binaural GVS was applied to ten healthy young subjects. Twenty-four trials, each containing a different galvanic input stimulus from among eight different frequency ranges, were conducted on each subject. Postural sway was evaluated through analysis of the center-of-pressure (COP) displacements under each subject's feet. Spectral analysis was performed on the galvanic stimuli and the COP displacement time series to calculate the coherence spectra. Significant coherence was found between the galvanic input signal and the anteroposterior COP displacement in some of the trials (i.e., at least one) in nine of the ten subjects. In general, the coherence values were highest for the mid-range frequencies that were tested, and lowest for the low- and high-range frequencies. However, the coherence values we obtained were lower than those we previously reported for stochastic bipolar binaural GVS and mediolateral sway. These differences may be due to fundamental characteristics of the vestibular system such as lower sensitivity to symmetric changes in afferent firing dynamics, and/or differences between the biomechanics of anteroposterior and mediolateral sway.

Systems and methods for reverse engineering models of biological networks

Abstract: The present invention provides methods and accompanying computer-based systems and computer-executable code stored on a computer-readable medium for constructing a model of a biological network. The invention further provides methods for performing sensitivity analysis on a biological network and for identifying major regulators of species in the network and of the network as a whole. In addition, the invention provides methods for identifying targets of a perturbation such as that resulting from exposure to a compound or an environmental change. The invention further provides methods for identifying phenotypic mediators that contribute to differences in phenotypes of biological systems.

A method and apparatus for enhancing neurophysiologic performance

Abstract: The invention features methods and apparatus for enhancing neurophysiologic performance, such as sensorimotor control and neuroplasticity. A preferred method involves inputting bias signals to sensory cells of a subject, thereby improving sensory cell function, while the subject is performing a predefined physical activity. A system used to practice the method of the invention includes a wearable device (500) to which is secured at least one repositionable signal input device (510) and a signal generator (514) that is communicatively coupled to the signal input devices.

Literacy and Literacies: Introduction: texts, power, and identity

Abstract: Puzzles and pluralities of literacy Literacy is a curious thing. It seems to envelope our lives and be central to modern living, yet most of humanity has done without it for most of human existence. As a term, it points to a striking range of possibilities – such that we now speak not only of “school literacy” and “vernacular literacy” but also “cultural literacy,” “computer literacy,” “moral literacy,” and even “emotional literacy” (Steiner, 1997). But the term is also subject to notable recent efforts to define and restrict its essence, for example, through legislating a particular way that reading or writing must be taught in school. As a field of study, literacy entangles some of the most difficult problems in social analysis – among them the question of text, that is, of language, situation, and meaning – yet it is also a very familiar topic, the source of many proclaimed crises and the subject of many slogans and sound-bites about how to live, raise children, and prepare for the rigors and excitements of the new century. Literacy often seems to pervade our lives. Increasing numbers of people make their living interacting with a computer screen. Many find reading a welcome escape, and they “bury” themselves in a good book, perhaps a romance or a futuristic fantasy or, if young, a tale of the wise doings of the cleverly marketed Harry Potter.

Literacy and Literacies: Conclusion: literacy lessons – beginnings, ends, and implications

Abstract: This development, coupled with that of anthropology and of the history of writing, teaches us that phonetic writing, the medium of the great metaphysical, scientific, technical, and economic adventure of the West, is limited in space and time and limits itself even as it is in the process of imposing its laws upon the cultural areas that had escaped it. (Derrida, 1976a, p. 10) It's our cultural fears – of internal decay, of loss of order, of diminishment – that weave into our assessments of literacy and scholastic achievement. (Rose, 1989, p. 7) Introduction In the preceding chapters we have engaged with a number of complex conceptual issues concerning literacy, in particular those of text, power, and identity, and we have developed our arguments via a wide range of ethnographic and historical cases. What we wish to do at this point is revisit certain of those issues, developing arguments and questions further, making connections between chapters, cases, and conceptual positions. That is, and against convention, we will try to make this conclusion an opening as much as a closing. Because the theme of the “origins” of literacy continues to fascinate both scholarship and popular culture, we will return to this topic by means of the Tolowa case with which our book opened. As we examine the late-twentieth-century advent of writing among these Northern California native people, we are brought to issues and questions raised by Derrida about the theme of origins in writing as well as to recent criticisms made by Goody about Derrida's relativist arguments concerning writing, reading, and books.

Move to the rhythm

Abstract: Many systems, from pendulums to fireflies, work in synchrony.

Noise-Enhanced Human Sensorimotor Function Using Stochastic Resonance to Enhance Somatosensation and Improve Performance of the Human Balance Control System

Abstract: omatosensory feedback is an important component of the balance control system. Older adults, patients with diabetic neuropathy, and patients with stroke exhibit a marked deficit in the perception of cutaneous and proprioceptive stimuli (e.g., see [1] and references therein). Such changes to the somatosensory system, which have been associated with increases in mechanoreceptor detection thresholds , may predispose individuals to falls, which are the most common cause of morbidity and mortality among older persons. Accordingly, there is a pressing need to develop bioengi-neering techniques and devices that improve sensorimotor function in older adults and patients with sensory deficits. Recently, it has been shown that noise can enhance the detection and transmission of weak signals in certain nonlinear systems, via a mechanism known as stochastic resonance (SR). The phenomenon of SR, which is counterintuitive given that noise has traditionally been viewed as a detriment to signal detection and transmission, is based on the concept that the flow of information through a system can be maximized by the presence of a particular, nonzero level of noise. SR was originally proposed in the context of global climate modeling as a possible explanation for the periodic recurrences of the Earth's ice ages [2], [3]. Since then, SR-type dynamics have been demonstrated in a variety of physical and biological systems [4]-[10], including rat cutaneous afferents [11] and human muscle spindles [12]. In this article, we review our work on using input noise (mechanical and electrical, respectively) to enhance somatosensation in humans [1], [13]-[16] and improve the performance of the human balance control system [17], [18]. We also discuss bioengineering applications and future directions for SR-based techniques and devices. As a first effort in this area, we designed a study to examine the effects of input noise on tactile sensation in humans. Specifically , we were interested in studying noise-mediated changes in the perception of subthreshold tactile stimuli. We hypothesized that the ability of an individual to detect a subthreshold tactile stimulus can be significantly enhanced by the presence of a particular, nonzero level of noise [13], [14]. To test this hypothesis, we conducted psychophysical experiments on ten healthy young subjects (age 18-31 years, mean 25 years). Local indentations were applied to the tip of each subject's right middle digit using a cylindrical probe (Figure 1). The protocol consisted of the presentation of: a) a subthreshold mechanical stimulus plus mechanical noise, or b) no mechanical stimulus …