Showing papers by "James J. Collins published in 2001"

Computational studies of gene regulatory networks: in numero molecular biology

Abstract: Remarkable progress in genomic research is leading to a complete map of the building blocks of biology Knowledge of this map is, in turn, setting the stage for a fundamental description of cellular function at the DNA level Such a description will entail an understanding of gene regulation, in which proteins often regulate their own production or that of other proteins in a complex web of interactions The implications of the underlying logic of genetic networks are difficult to deduce through experimental techniques alone, and successful approaches will probably involve the union of new experiments and computational modelling techniques

Designer gene networks: Towards fundamental cellular control

Abstract: The engineered control of cellular function through the design of synthetic genetic networks is becoming plausible. Here we show how a naturally occurring network can be used as a parts list for artificial network design, and how model formulation leads to computational and analytical approaches relevant to nonlinear dynamics and statistical physics. We first review the relevant work on synthetic gene networks, highlighting the important experimental findings with regard to genetic switches and oscillators. We then present the derivation of a deterministic model describing the temporal evolution of the concentration of protein in a single-gene network. Bistability in the steady-state protein concentration arises naturally as a consequence of autoregulatory feedback, and we focus on the hysteretic properties of the protein concentration as a function of the degradation rate. We then formulate the effect of an external noise source which interacts with the protein degradation rate. We demonstrate the utility of such a formulation by constructing a protein switch, whereby external noise pulses are used to switch the protein concentration between two values. Following the lead of earlier work, we show how the addition of a second network component can be used to construct a relaxation oscillator, whereby the system is driven around the hysteresis loop. We highlight the frequency dependence on the tunable parameter values, and discuss design plausibility. We emphasize how the model equations can be used to develop design criteria for robust oscillations, and illustrate this point with parameter plots illuminating the oscillatory regions for given parameter values. We then turn to the utilization of an intrinsic cellular process as a means of controlling the oscillations. We consider a network design which exhibits self-sustained oscillations, and discuss the driving of the oscillator in the context of synchronization. Then, as a second design, we consider a synthetic network with parameter values near, but outside, the oscillatory boundary. In this case, we show how resonance can lead to the induction of oscillations and amplification of a cellular signal. Finally, we construct a toggle switch from positive regulatory elements, and compare the switching properties for this network with those of a network constructed using negative regulation. Our results demonstrate the utility of model analysis in the construction of synthetic gene regulatory networks.

Enhancing human balance control with galvanic vestibular stimulation

Abstract: With galvanic vestibular stimulation (GVS), electrical current is delivered transcutaneously to the vestibular afferents through electrodes placed over the mastoid bones. This serves to modulate the continuous firing levels of the vestibular afferents, and causes a standing subject to lean in different directions depending on the polarity of the current. Our objective in this study was to test the hypothesis that the sway response elicited by GVS can be used to reduce the postural sway resulting from a mechanical perturbation. Nine subjects were tested for their postural responses to both galvanic stimuli and support-surface translations. Transfer-function models were fit to these responses and used to calculate a galvanic stimulus that would act to counteract sway induced by a support-surface translation. The subjects' responses to support-surface translations, without and with the stabilizing galvanic stimulus, were then measured. With the stabilizing galvanic stimulus, all subjects showed significant reductions in both sway amplitude and sway latency. Thus, with GVS, subjects maintained a more erect stance and followed the support-surface displacement more closely. These findings suggest that GVS could possibly form the basis for a vestibular prosthesis by providing a means through which an individual's posture can be systematically controlled.

A review and meta‐analysis of formaldehyde exposure and pancreatic cancer

Abstract: Background Most reviews on the carcinogenicity of formaldehyde have focused on cancers of the respiratory tract. Two recent studies have suggested that exposure to formaldehyde may increase the risk for pancreatic cancer. Methods We examine 14 epidemiology studies of workers exposed to formaldehyde where pancreatic cancer rates were reported and use meta-analytic techniques to summarize the findings. We also rank formaldehyde exposures for the industries in these studies. Results We found a small increase of pancreatic cancer risk in the studies overall (meta Relative Risk [mRR] 1.1, 95%CI 1.0–1.3); however, this increased risk was limited to embalmers (mRR 1.3, 95%CI 1.0–1.6) and pathologists and anatomists (mRR 1.3, 95%CI 1.0–1.7). There was no increased risk among industrial workers (mRR 0.9, 95%CI 0.8–1.1) who on average had the highest formaldehyde exposures. Conclusions A small increased risk of pancreatic cancer from formaldehyde exposure cannot be ruled out from the studies examined. However, the null findings among industrial workers and the lack of biological plausibility would argue against formaldehyde as a cause. The increased risk of pancreatic cancer among embalmers, pathologists, and anatomists may be due to a diagnostic bias or to occupational exposures other than formaldehyde in these professions. Am. J. Ind. Med. 39:336–345, 2001. © 2001 Wiley-Liss, Inc.

Predicting cerebral blood flow response to orthostatic stress from resting dynamics: effects of healthy aging

Abstract: The transfer function relating arterial pressure (AP) to cerebral blood flow velocity (CBFV) during resting conditions has been used to predict the CBFV response to hypotension. We hypothesized tha...

Protein interactions. Unspinning the web.

Abstract: A large-scale study of the protein network in yeast cells demonstrates the merit of taking an integrated approach to cellular dynamics, and shows the value of databases.

Reevaluation of lung cancer risk in the acrylonitrile cohort study of the National Cancer Institute and the National Institute for Occupational Safety and Health.

Abstract: Objectives The present study provides additional analyses of data obtained earlier on lung cancer risk among workers with acrylonitrile exposure. Methods The original authors provided the data. For total mortality and the cancer sites of a priori interest (lung, stomach, brain, breast, prostate, and the lymphatic and hematopoietic systems), standardized mortality ratios (SMR) and 95% confidence intervals (95% CI) were computed, the total United States and surrounding counties being used as standard populations. Regional rate-based SMR values were also computed between lung cancer and cumulative acrylonitrile exposure. Results Except for lung cancer, the external comparisons corroborated the earlier internal comparisons (no increased cancer mortality risk). For lung cancer, the external comparisons revealed death deficits for the unexposed workers (SMR 0.68, 95% CI 0.5-0.9) and all categories of acrylonitrile-exposed workers. The SMR obtained using external rates and the most exposed group (SMR 0.92, 95% CI 0.6-1.4) differed from the corresponding relative risk (RR) of the internal rates (RR 1.5, 95% CI 0.9-2.4). Conclusions The analysis of the present study provides little evidence that acrylonitrile exposure increases the mortality risk of cancers of a priori interest, including lung cancer. The lung cancer findings of the external comparison differed from the earlier findings of the internal comparisons. Selection bias (as the healthy worker effect) was probably not responsible. Additional follow-up and analyses, especially of the unexposed workers with low lung cancer rates, may help elucidate the internal and external comparison differences. Results from both comparisons should be presented when the relative risks differ markedly, as both have advantages and disadvantages.

Selling the Market Educational Standards, Discourse and Social Inequality

Abstract: The call for national and state-level educational standards has swept across the American educational scene in the last 15 years. Using a language of competition, fair play and equal treatment, standards advocates have captured a broad spectrum of both conservative and liberal support. Drawing upon journalistic reports, advocacy documents and interview data, the A. presents an analysis of interconnected aspects of the evolution of educational reform discourse, in particular, advocacy from the leadership of a national teachers' union and classroom teachers' situated responses to ongoing changes. Critically appropriating from Fairclough's analytic schema and commensurable concepts in Silverstein and Urban, he analyzes interactional figures and socio-political themes involved in the elite and non-elite discourse of standards, with particular focus on the neo-liberal trope of a new era of work and associated fears of increasing inequality. He concludes by assessing the differing strengths of the two frameworks as well as the role of discourse analysis more generally in critical social inquiry.

Discourse and Critique: Part One Introduction

Abstract: As the recent republication of some of Dell Hymes’s papers from the 1960s and early 1970s makes clear, programmes for linking social critique to empirical research on language and discourse reach back at least 30 or 40 years (Hymes, 1969, 1996). So why ‘discourse and critique’ right now? The factors motivating the present collection are broadly two-fold. First, there has been surprisingly little transatlantic contact between the traditions of discourse analysis in Europe and North America that are committed to reflexive investigation of constitutive relations between language, ideology and inequality.1 Both critical discourse analysis (CDA) in Europe and linguistic anthropology (LA) in the USA are concerned with the links between language, discourse and larger social processes, with the problems of how to capture this relationship, and with the politics of research itself (see Blommaert and Bulcaen, 2000, for a fuller discussion), but in the absence of any dialogue between them, the differences are more striking than the similarities. Whereas CDA generally centres on lexico-grammatical meaning in written and mass-mediated texts, LA leans much more to ethnographically grounded analysis of indexical meaning in face-to-face interaction, and where false consciousness and ideology-as-mystification

Wavelets of excitability in sensory neurons.

Abstract: We have investigated variations in the excitability of mammalian cutaneous mechanoreceptor neurons. We focused on the phase dynamics of an action potential relative to a periodic stimulus, showing that the excitability of these sensory neurons has interesting nonstationary oscillations. Using a wavelet analysis, these oscillations were characterized through the depiction of their period as a function of time. It was determined that the induced oscillations are weakly dependent on the stimulus frequency, and that lower temperatures significantly reduce the frequency of the phase response. Our results reveal novel excitability properties in sensory neurons, and, more generally, could prove significant in the deduction of mechanistic attributes underlying the nonstationary excitability in neuronal systems. Since peripheral neurons feed information to the CNS, variable responses observed in higher regions may be generated in part at the site of sensory detection.

Chapter 6 Controlling cardiac arrhythmias: The relevance of nonlinear dynamics

Abstract: Publisher Summary This chapter outlines the basic electrophysiological properties of the heart, the nature of cardiac arrhythmias, and the analysis and control of arrhythmias. In addition, to focusing on nonlinear dynamics, the chapter discusses the remarkable advancements made from within the medical community to give dynamicists a better appreciation of the current state of the art in arrhythmia management—its strengths, weaknesses, and areas in which nonlinear dynamics might have the greatest impact. The chapter emphasizes those arrhythmias for which the field of nonlinear dynamics is particularly relevant and describes the advantages and disadvantages of the current clinical methods of suppressing or curing such arrhythmias. It describes some recent advancement in nonlinear dynamical control of temporal arrhythmias that could lead to improved arrhythmia management.

Designer Gene Networks: Towards Fundamental Cellular Control

Abstract: The engineered control of cellular function through the design of synthetic genetic networks is becoming plausible. Here we show how a naturally occurring network can be used as a parts list for artificial network design, and how model formulation leads to computational and analytical approaches relevant to nonlinear dynamics and statistical physics.