Showing papers by "James J. Collins published in 2011"
TL;DR: It is proposed that cellular decision making is one of at least three key processes underlying development at various scales of biological organization.
919 citations
01 Mar 2011
TL;DR: In this paper, the authors review several examples of cellular decision-making from viruses, bacteria, yeast, lower metazoans and mammals, highlighting the role of regulatory network structure and molecular noise.
Abstract: Cellular decision-making is the process wherein cells assume different, functionally important and heritable fates without an associated genetic or environmental difference. Such stochastic cell-fate decisions generate non-genetic cellular diversity, which may be critical for metazoan development as well as optimized microbial resource utilization and survival in a fluctuating, frequently stressful environment. Here we review several examples of cellular decision-making from viruses, bacteria, yeast, lower metazoans and mammals, highlighting the role of regulatory network structure and molecular noise. We propose that cellular decision-making is one of at least three key processes underlying development at various scales of biological organization.
786 citations
TL;DR: It is shown that specific metabolic stimuli enable the killing of both Gram-negative and Gram-positive bacterial persisters with aminoglycosides, and this approach can improve the treatment of chronic infections in a mouse urinary tract infection model.
Abstract: Bacterial persistence is a state in which a sub-population of dormant cells, or 'persisters', tolerates antibiotic treatment. Bacterial persisters have been implicated in biofilms and in chronic and recurrent infections. Despite this clinical relevance, there are currently no viable means for eradicating persisters. Here we show that specific metabolic stimuli enable the killing of both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) persisters with aminoglycosides. This potentiation is aminoglycoside-specific, it does not rely on growth resumption and it is effective in both aerobic and anaerobic conditions. It proceeds by the generation of a proton-motive force which facilitates aminoglycoside uptake. Our results demonstrate that persisters, although dormant, are primed for metabolite uptake, central metabolism and respiration. We show that aminoglycosides can be used in combination with specific metabolites to treat E. coli and S. aureus biofilms. Furthermore, we demonstrate that this approach can improve the treatment of chronic infections in a mouse urinary tract infection model. This work establishes a strategy for eradicating bacterial persisters that is based on metabolism, and highlights the importance of the metabolic environment to antibiotic treatment.
756 citations
TL;DR: Extended passage of some iPSC clones in culture did not improve their epigenetic resemblance to embryonic stem cells, implying that some human iPSCs retain a residual 'epigenetic memory' of their tissue of origin.
Abstract: Mouse induced pluripotent stem (iPS) cells have been shown to retain an epigenetic 'memory' of their cell type of origin. Kim et al. study this question in human cells and document both incomplete erasure of methylation and aberrant de novo methylation during reprogramming.
573 citations
TL;DR: Advances in the biomedical application of synthetic biology are highlighted and the field’s clinical potential is discussed.
Abstract: Synthetic biology is an emerging field focused on engineering biomolecular systems and cellular capabilities for a variety of applications. Substantial progress began a little over a decade ago with the creation of synthetic gene networks inspired by electrical engineering. Since then, the field has designed and built increasingly complex circuits and constructs and begun to use these systems in a variety of settings, including the clinic. These efforts include the development of synthetic biology therapies for the treatment of infectious diseases and cancer, as well as approaches in vaccine development, microbiome engineering, cell therapy, and regenerative medicine. Here, we highlight advances in the biomedical application of synthetic biology and discuss the field’s clinical potential.
381 citations
TL;DR: The hypothesis that each bacterial population may contain a diverse collection of persisters is posed and engineering strategies for persister eradication are discussed.
189 citations
TL;DR: It is demonstrated that tunable signal processing is inherent to minimal MAPK modules and elucidates principles for rational design of synthetic signaling systems.
149 citations
TL;DR: A battery of commercially available stains, antibodies and fluorescently labeled lectins, many of which have not been described previously for analyzing schistosomes, are screened for their ability to label various cell and tissue types in the cercarial stage of S. mansoni.
Abstract: Schistosomiasis (bilharzia) is a tropical disease caused by trematode parasites (Schistosoma) that affects hundreds of millions of people in the developing world. Currently only a single drug (praziquantel) is available to treat this disease, highlighting the importance of developing new techniques to study Schistosoma. While molecular advances, including RNA interference and the availability of complete genome sequences for two Schistosoma species, will help to revolutionize studies of these animals, an array of tools for visualizing the consequences of experimental perturbations on tissue integrity and development needs to be made widely available. To this end, we screened a battery of commercially available stains, antibodies and fluorescently labeled lectins, many of which have not been described previously for analyzing schistosomes, for their ability to label various cell and tissue types in the cercarial stage of S. mansoni. This analysis uncovered more than 20 new markers that label most cercarial tissues, including the tegument, the musculature, the protonephridia, the secretory system and the nervous system. Using these markers we present a high-resolution visual depiction of cercarial anatomy. Examining the effectiveness of a subset of these markers in S. mansoni adults and miracidia, we demonstrate the value of these tools for labeling tissues in a variety of life-cycle stages. The methodologies described here will facilitate functional analyses aimed at understanding fundamental biological processes in these parasites.
127 citations
TL;DR: This work validate a predicted role for IsrA and GlmZ in the SOS response, and expands on current knowledge of the GcvB sRNA, demonstrating its broad role in the regulation of amino acid metabolism and transport, and shows that a network-based approach can be used to identify the cellular function of sRNAs and characterize the relationship between sRNAAs and transcription factors.
Abstract: Small RNAs (sRNAs) are important components of posttranscriptional regulation. These molecules are prevalent in bacterial and eukaryotic organisms, and involved in a variety of responses to environmental stresses. The functional characterization of sRNAs is challenging and requires highly focused and extensive experimental procedures. Here, using a network biology approach and a compendium of gene expression profiles, we predict functional roles and regulatory interactions for sRNAs in Escherichia coli. We experimentally validate predictions for three sRNAs in our inferred network: IsrA, GlmZ, and GcvB. Specifically, we validate a predicted role for IsrA and GlmZ in the SOS response, and we expand on current knowledge of the GcvB sRNA, demonstrating its broad role in the regulation of amino acid metabolism and transport. We also show, using the inferred network coupled with experiments, that GcvB and Lrp, a transcription factor, repress each other in a mutually inhibitory network. This work shows that a network-based approach can be used to identify the cellular function of sRNAs and characterize the relationship between sRNAs and transcription factors.
97 citations
TL;DR: Two mechanisms that confer antibiotic tolerance in bacteria are described that are similar to those described in previous studies of eukaryotic and prokaryotic cells that developed efficient endogenous antioxidant mechanisms.
Abstract: In living organisms, aerobic metabolism produces toxic reactive oxygen species (ROS) ( 1 ). Life can thus be seen as a balance between metabolic rate and a cell's ability to detoxify ROS. This understanding has led to intense public interest and increased consumption of dietary antioxidants. Although the effectiveness of antioxidant supplements is not yet established, there is no doubt that eukaryotic and prokaryotic cells have developed efficient endogenous antioxidant mechanisms ( 1 , 2 ). On pages 982 and 986 of this issue, Nguyen et al. ( 3 ) and Shatalin et al. ( 4 ) describe two such mechanisms that confer antibiotic tolerance in bacteria.
55 citations
TL;DR: A whole mount in situ hybridization method that can be used to identify the tissue-specific expression of transcripts in S. mansoni, and can be adapted to screen multiple transcripts, thus identifying novel targets for drugs or vaccines.
TL;DR: Recent advances gleaned from application of global "omics" techniques to dissect the molecular mechanisms that define the pluripotent state of ESCs and iPSCs are discussed.
Abstract: Embryonic stem cells (ESCs) first derived from the inner cell mass of blastocyst-stage embryos have the unique capacity of indefinite self-renewal and potential to differentiate into all somatic cell types. Similar developmental potency can be achieved by reprogramming differentiated somatic cells into induced pluripotent stem cells (iPSCs). Both types of pluripotent stem cells provide great potential for fundamental studies of tissue differentiation, and hold promise for disease modeling, drug development, and regenerative medicine. Although much has been learned about the molecular mechanisms that underlie pluripotency in such cells, our understanding remains incomplete. A comprehensive understanding of ESCs and iPSCs requires the deconstruction of complex transcription regulatory networks, epigenetic mechanisms, and biochemical interactions critical for the maintenance of self-renewal and pluripotency. In this review, we will discuss recent advances gleaned from application of global “omics” techniques...
TL;DR: In this article, a critical-ethnographic approach to language policy is proposed to transform persistent linguistic inequalities in the USA, based on Hymes's "report from an underdeveloped country" (the USA).
Abstract: This essay updates Dell Hymes's “Report from an Underdeveloped Country” (the USA), positioning our analysis in the New Language Policy Studies. Taking up Hymes's call for comparative, critical studies of language use, we examine three cases, organizing our analysis around Hymes's questions: What “counts” as a language, a language problem, and “proper” language use? We conclude with a final question suggested by Hymes's Report: How can a critical-ethnographic approach to language policy transform persistent linguistic inequalities? [Dell Hymes, new language policy studies, ethnography of communication, linguistic inequality, educational linguistics]
TL;DR: Overall, there were fewer cancer cases than expected, and a non statistically significant increase in the number of NHL cases, and no clear patterns of NHL risk with period of hire and histology subtypes.
Abstract: Despite showing no evidence of carcinogenicity in laboratory animals, the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) has been associated with non-Hodgkin lymphoma (NHL) in some human epidemiology studies, albeit inconsistently. We matched an existing cohort of 2,4-D manufacturing employees with cancer registries in three US states resulting in 244 cancers compared to 276 expected cases. The Standardized Incidence Ratio (SIR) for the 14 NHL cases was 1.36 (95% Confidence Interval (CI) 0.74–2.29). Risk estimates were higher in the upper cumulative exposure and duration subgroups, yet not statistically significant. There were no clear patterns of NHL risk with period of hire and histology subtypes. Statistically significant results were observed for prostate cancer (SIR = 0.74, 95% CI 0.57–0.94), and “other respiratory” cancers (SIR = 3.79, 95% CI 1.22–8.84; 4 of 5 cases were mesotheliomas). Overall, we observed fewer cancer cases than expected, and a non statistically significant increase in the number of NHL cases.
TL;DR: Findings lend credence to the theory that prolonged respiratory effects do not occur with doses less than 150 ppm-minutes and found no relationship between phosgene exposure and the presence of symptoms 30 days after exposure.
Abstract: Objective In 2004, The American Chemistry Council Phosgene Panel established a phosgene exposure registry among US phosgene producers with the primary purpose of monitoring health outcome information for workers with acute exposure. Methods We examine symptoms among 338 workers with phosgene exposure. The phosgene exposures averaged 8.3 ppm-minutes ranging up to 159 ppm-minutes with most exposures below 10 ppm-minutes. Results We found that the level of phosgene exposure in ppm-minutes was related to workers reporting mostly irritation symptoms of the nose, throat and eyes within 48 hours of exposure. However, we found no relationship between phosgene exposure and the presence of symptoms 30 days after exposure. Conclusions These findings lend credence to the theory that prolonged respiratory effects do not occur with doses less than 150 ppm-minutes.
TL;DR: The authors reviewed literature on social reproduction in education, discusses the decline of the paradigm, and argues for its continuing relevance, and examines reproductive and transformative aspects of cross-linguistic literacy practices involving young people from three diasporic communities in the United States, presenting multi-leveled analyses that investigate what is reproduced or transformed by situated literacy practices and how institution-level processes shape such practices.
TL;DR: The low SMRs observed in this study are likely due to differential smoking between the cohort and the background population, and future considerations to control for the HWE should take this into account.
Abstract: BACKGROUND Occupational studies typically observe a 20% deficit in overall mortality, broadly characterized as the healthy worker effect (HWE). Components of the HWE may be addressed by various analytical approaches. AIMS To explore the HWE in a modern industrial cohort. METHODS Standardized mortality ratios (SMRs) were calculated for 114,683 US chemical industry employees, who worked at least 3 days between 1960 and 2005. RESULTS SMRs were 79 (95% confidence interval 78-80) for all causes, 81 (95% confidence interval 79-82) for heart disease, 70 (95% confidence interval 67-73) for non-malignant respiratory disease, 83 (95% confidence interval 81-85) for smoking-related cancers (buccal, cervix, oesophagus, stomach, pancreas, lung, larynx, bladder and kidney) combined and 97 (95% confidence interval 95-100) for other cancers. CONCLUSIONS The low SMRs observed in this study are likely due to differential smoking between the cohort and the background population. Future considerations to control for the HWE should take this into account.
TL;DR: This issue of Molecular Cell, Hart et al. (2011) investigate how E. coli robustly controls nitrogen assimilation, and show how the bacteria encounter fluctuations in both their external and internal environments.
TL;DR: James J. Collins' research group works in synthetic biology and systems biology, with a particular focus on network biology approaches to antibiotic action and bacterial defense mechanisms.
Journal Article•
TL;DR: The mortality rates for an occupational cohort was favorable and robust and topics of historical concern at specific locations that may influence the cohort's appropriateness for future studies are discussed.
Abstract: Objective: To evaluate the mortality for an occupational cohort and discuss its suitability as an internal comparison population. Methods: The study included 114,683 employees who worked at 1 of 25 US locations between January 1, 1960, and December 31, 2005. Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) were calculated based on US rates. Results: The SMRs were significantly favorable for all causes, malignant neoplasms, heart disease, and external causes. The most common cancer sites were lung in men (SMR = 83, 95% CI = 80 to 86), and breast in women (SMR = 94, 95% CI = 80 to 111). Conclusions: Overall, the mortality rates were favorable and robust. Discussed within are topics of historical concern at specific locations that may influence the cohort's appropriateness for future studies.