Showing papers by "James J. Collins published in 2004"

Programmable cells: Interfacing natural and engineered gene networks

Abstract: Novel cellular behaviors and characteristics can be obtained by coupling engineered gene networks to the cell's natural regulatory circuitry through appropriately designed input and output interfaces. Here, we demonstrate how an engineered genetic circuit can be used to construct cells that respond to biological signals in a predetermined and programmable fashion. We employ a modular design strategy to create Escherichia coli strains where a genetic toggle switch is interfaced with: (i) the SOS signaling pathway responding to DNA damage, and (ii) a transgenic quorum sensing signaling pathway from Vibrio fischeri. The genetic toggle switch endows these strains with binary response dynamics and an epigenetic inheritance that supports a persistent phenotypic alteration in response to transient signals. These features are exploited to engineer cells that form biofilms in response to DNA-damaging agents and cells that activate protein synthesis when the cell population reaches a critical density. Our work represents a step toward the development of "plug-and-play" genetic circuitry that can be used to create cells with programmable behaviors.

Engineered riboregulators enable post-transcriptional control of gene expression

Abstract: Recent studies have demonstrated the important enzymatic, structural and regulatory roles of RNA in the cell. Here we present a post-transcriptional regulation system in Escherichia coli that uses RNA to both silence and activate gene expression. We inserted a complementary cis sequence directly upstream of the ribosome binding site in a target gene. Upon transcription, this cis-repressive sequence causes a stem-loop structure to form at the 5'-untranslated region of the mRNA. The stem-loop structure interferes with ribosome binding, silencing gene expression. A small noncoding RNA that is expressed in trans targets the cis-repressed RNA with high specificity, causing an alteration in the stem-loop structure that activates expression. Such engineered riboregulators may lend insight into mechanistic actions of endogenous RNA-based processes and could serve as scalable components of biological networks, able to function with any promoter or gene to directly control gene expression.

Reliability and validity of the Stanford Presenteeism Scale.

Abstract: Objective:This study reports the reliability and validity of the 13-item Stanford Presenteeism Scale (SPS). The SPS differs from similar scales by focusing on knowledge-based and production-based workers.Methods:Data were obtained from administrative and medical claims databases and from a s

Method and apparatus for improving human balance and gait and preventing foot injury

Abstract: A method and wearable system and for enhancing human balance and gait and preventing foot injury through neurological stimulation of the foot and the ankle. Subthreshold stimulation for neurosensory enhancement is provided via electrodes or vibrational actuators, or combination thereof, disposed in or on a wearable a platform, such as an insole, sock shoe, removable shoe insert, or applied without the support of a platform, to the skin surface of an individual. Suprathreshold stimulation for therapeutic purposes, such as improving blood flow, is also provided by the vibrational actuators. The actuators and electrodes are driven by bias signals generated by a bias signal generator that is coupled to a controller. The signal generator under the control of the controller is adapted to generate a non-deterministic random signal, a repetitive pattern or series of patterns. The controller optionally includes a communication port for interfacing with an external computer for purposes of optimizing and programming the controller. The wearable system is powered by a power source.

Evolving complex dynamics in electronic models of genetic networks

Abstract: Ordinary differential equations are often used to model the dynamics and interactions in genetic networks. In one particularly simple class of models, the model genes control the production rates of products of other genes by a logical function, resulting in piecewise linear differential equations. In this article, we construct and analyze an electronic circuit that models this class of piecewise linear equations. This circuit combines CMOS logic and RC circuits to model the logical control of the increase and decay of protein concentrations in genetic networks. We use these electronic networks to study the evolution of limit cycle dynamics. By mutating the truth tables giving the logical functions for these networks, we evolve the networks to obtain limit cycle oscillations of desired period. We also investigate the fitness landscapes of our networks to determine the optimal mutation rate for evolution.

Mortality update of workers exposed to acrylonitrile in The Netherlands.

Abstract: To study the possible carcinogenic effects of acrylonitrile, we updated the follow up of a cohort of 2842 acrylonitrile workers. The comparison group consisted of 3961 workers from a nitrogen fixation plant. Industrial hygiene assessments quantified past exposure to acrylonitrile, 8-hour averages as well as peak exposure, the use of personal protective equipment, and exposure to other potential carcinogenic agents. Standardized mortality ratios were calculated to adjust for the effect of age distribution, length of follow up, and temporal changes in background mortality rates. Cumulative dose-effect relations were determined for 3 exposure categories and 3 latency periods. The results show that no cancer excess seems related to exposure to acrylonitrile. This additional follow up of a cohort of 2842 workers exposed to acrylonitrile further supports the notion that occupational exposures to acrylonitrile that have occurred in the past have not noticeably increased workers' cancer mortality rates.

A risk assessment for occupational acrylonitrile exposure using epidemiology data.

Abstract: The extensive data from the Blair et al.((1)) epidemiology study of occupational acrylonitrile exposure among 25460 workers in eight plants in the United States provide an excellent opportunity to update quantitative risk assessments for this widely used commodity chemical. We employ the semiparametric Cox relative risk (RR) regression model with a cumulative exposure metric to model cause-specific mortality from lung cancer and all other causes. The separately estimated cause-specific cumulative hazards are then combined to provide an overall estimate of age-specific mortality risk. Age-specific estimates of the additional risk of lung cancer mortality associated with several plausible occupational exposure scenarios are obtained. For age 70, these estimates are all markedly lower than those generated with the cancer potency estimate provided in the USEPA acrylonitrile risk assessment.((2)) This result is consistent with the failure of recent occupational studies to confirm elevated lung cancer mortality among acrylonitrile-exposed workers as was originally reported by O'Berg,((3)) and it calls attention to the importance of using high-quality epidemiology data in the risk assessment process.

Re: Mortality From Lymphohematopoietic Malignancies Among Workers in Formaldehyde Industries

Abstract: The study described in the article byHauptmann et al. (1) has severalstrengths, including large size, long fol-low-up, and attempts to control for po-tentially important confounding factors.However, the study does not provideconclusive evidence of a causal associ-ation between formaldehyde exposureand leukemia for several reasons. In par-ticular, the large relative risks (RRs) re-ported for the internal comparison strat-ified by exposure category need to bereconciled with the external compari-sons in which the standardized mortalityratio (SMR) for all lymphohematopoi-etic neoplasms in formaldehyde-ex-posed workers is 0.8 (95% confidenceinterval [CI] 0.7 to 0.9). We haveestimated SMRs for leukemia and otherlympohematopoietic malignancies forthe peak formaldehyde exposure catego-ries shown in table 3 of Hauptmann etal. (1). These SMRs (Table 1) suggestthat mortality from lymphohematopoi-etic malignancies is not higher thanwould be expected in those workerswith a peak formaldehyde exposure of 4ppm or more, but rather is lower thanwould be expected in workers in thelowest exposure category of less than 2ppm (SMR 0.6, 95% CI 0.4 to 0.7).Similar conclusions may be drawn fromthe leukemia findings.Additionally, we point out that theassignment of peak exposure was basedprimarily on professional judgment, noton actual measurements. Such an as-signment makes this exposure the weak-est of the four exposure metrics used inthe study by Hauptmann et al. (1) rela-tive to supporting data, and this expo-sure is typically the most difficult expo-sure metric to estimate in the absence ofdetailed measurements.Hauptmann et al. (1) briefly discussthe biologic evidence relevant to theirhypothesis of formaldehyde-inducedlymphohematopoietic cancer, but theyconclude that the evidence is inconsis-tent. However, this conclusion is inconflict with substantial experimentaldata showing that, under controlledexposures, there is no increase in theconcentration of formaldehyde in theblood of humans (2 ppm), monkeys (6ppm), or rats (15 ppm) (2,3) and thatformaldehyde does not appear to in-duce cancer via inhalation at sitesother than the respiratory tract (4).These results strongly suggest that in-haled formaldehyde is rapidly metab-olized in the respiratory tract, does notreach the bone marrow, and is there-fore unlikely to induce distant-site tox-icity including leukemia.Finally, discrepancies in the datafrom available industrial studies sug-gest that the findings of Hauptmann etal. (1) may be due to chance, someuncontrolled confounding exposure, oran inappropriate comparison group.For example, a large study of workersexposed to formaldehyde in the U.K.(5) reports no increased risk for leuke-mia in the entire study cohort (SMR0.9, 95% CI 0.6 to 1.3) or amongworkers with the highest formalde-hyde exposures (SMR 0.7, 95% CI 0.3 to 1.4).Thus, we believe that the findingsof Hauptmann et al. (1) need to becritically assessed in light of externalcomparisons, existing biologic evi-dence, the findings of other studies,and a more complete understanding ofthe exposure metrics and classificationparameters used. Until these issues aremeaningfully addressed, questionswill continue to be raised about theoverall significance of the findingsreported.M

Communication of epidemiology study results by industry: the Dow Chemical Company approach.

Abstract: Communicating epidemiology study results to subjects, affected workers, and community members is an important part of compliance and alignment with our company's policies, industry's Responsible Care® Principles, and the doctrines of Good Epidemiology Practices It is the responsibility of the investigators to interpret their research appropriately for each audience, and to assure that all who have a need or right to know get information in a form meaningful to them We discuss study communication with examples from a recent evaluation of communication efforts within Dow and our experience with occupational and community studies on dioxin We also discuss how we currently structure worker and community communication based on this experience Since each Dow protocol must include a communication plan, when we agree to undertake a study, we are also agreeing to communicate study results Depending upon the nature and type of the study, there may also be some prestudy communication We encourage all investigators to share the results of their studies more broadly than just scientific publication and plan for the study communication before the study is initiated

Apparatus for improving human balance and gait and preventing foot injury

Abstract: not available for EP1608303Abstract of corresponding document: WO2004080528A method and wearable system and for enhancing human balance and gait and preventing foot injury through neurological stimulation of the foot and the ankle. Subthreshold stimulation for neurosensory enhancement is provided via electrodes or vibrational actuators, or combination thereof, disposed in or on a wearable a platform, such as an insole, sock shoe, removable shoe insert, or applied without the support of a platform, to the skin surface of an individual. Suprathreshold stimulation for therapeutic purposes, such as improving blood flow, is also provided by the vibrational actuators. The actuators and electrodes are driven by bias signals generated by a bias signal generator that is coupled to a controller. The signal generator under the control of the controller is adapted to generate a non-deterministic random signal, a repetitive pattern or series of patterns. The controller optionally includes a communication port for interfacing with an external computer for purposes of optimizing and programming the controller. The wearable system is powered by a power source.