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Phase-Locked Signals Elucidate Circuit Architecture of an Oscillatory Pathway
Andreja Jovic,Bryan Howell,Michelle Cote,Susan M. Wade,Khamir Mehta,Atsushi Miyawaki,Richard R. Neubig,Jennifer J. Linderman ,Shuichi Takayama
PLOS Computational Biology , 2010, DOI: 10.1371/journal.pcbi.1001040
Abstract: This paper introduces the concept of phase-locking analysis of oscillatory cellular signaling systems to elucidate biochemical circuit architecture. Phase-locking is a physical phenomenon that refers to a response mode in which system output is synchronized to a periodic stimulus; in some instances, the number of responses can be fewer than the number of inputs, indicative of skipped beats. While the observation of phase-locking alone is largely independent of detailed mechanism, we find that the properties of phase-locking are useful for discriminating circuit architectures because they reflect not only the activation but also the recovery characteristics of biochemical circuits. Here, this principle is demonstrated for analysis of a G-protein coupled receptor system, the M3 muscarinic receptor-calcium signaling pathway, using microfluidic-mediated periodic chemical stimulation of the M3 receptor with carbachol and real-time imaging of resulting calcium transients. Using this approach we uncovered the potential importance of basal IP3 production, a finding that has important implications on calcium response fidelity to periodic stimulation. Based upon our analysis, we also negated the notion that the Gq-PLC interaction is switch-like, which has a strong influence upon how extracellular signals are filtered and interpreted downstream. Phase-locking analysis is a new and useful tool for model revision and mechanism elucidation; the method complements conventional genetic and chemical tools for analysis of cellular signaling circuitry and should be broadly applicable to other oscillatory pathways.
Physico-Chemical Evaluation of Rationally Designed Melanins as Novel Nature-Inspired Radioprotectors
Andrew D. Schweitzer, Robertha C. Howell, Zewei Jiang, Ruth A. Bryan, Gary Gerfen, Chin-Cheng Chen, Dennis Mah, Sean Cahill, Arturo Casadevall, Ekaterina Dadachova
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0007229
Abstract: Background Melanin, a high-molecular weight pigment that is ubiquitous in nature, protects melanized microorganisms against high doses of ionizing radiation. However, the physics of melanin interaction with ionizing radiation is unknown. Methodology/Principal Findings We rationally designed melanins from either 5-S-cysteinyl-DOPA, L-cysteine/L-DOPA, or L-DOPA with diverse structures as shown by elemental analysis and HPLC. Sulfur-containing melanins had higher predicted attenuation coefficients than non-sulfur-containing melanins. All synthetic melanins displayed strong electron paramagnetic resonance (2.14·1018, 7.09·1018, and 9.05·1017 spins/g, respectively), with sulfur-containing melanins demonstrating more complex spectra and higher numbers of stable free radicals. There was no change in the quality or quantity of the stable free radicals after high-dose (30,000 cGy), high-energy (137Cs, 661.6 keV) irradiation, indicating a high degree of radical stability as well as a robust resistance to the ionizing effects of gamma irradiation. The rationally designed melanins protected mammalian cells against ionizing radiation of different energies. Conclusions/Significance We propose that due to melanin's numerous aromatic oligomers containing multiple π-electron system, a generated Compton recoil electron gradually loses energy while passing through the pigment, until its energy is sufficiently low that it can be trapped by stable free radicals present in the pigment. Controlled dissipation of high-energy recoil electrons by melanin prevents secondary ionizations and the generation of damaging free radical species.
Controversies in hormonal adjuvant therapy for premenopausal patients
A Howell
Breast Cancer Research , 2009, DOI: 10.1186/bcr2275
Current status of adjuvant endocrine therapy for premenopausal patients with primary breast cancer
A Howell
Breast Cancer Research , 2007, DOI: 10.1186/bcr1695
Tamoxifen resistance and adjuvant hormone therapy
A Howell
Breast Cancer Research , 2005, DOI: 10.1186/bcr1223
The emerging breast cancer epidemic: early diagnosis and treatment
Anthony Howell
Breast Cancer Research , 2010, DOI: 10.1186/bcr2739
Abstract: Whereas less than one-third of women diagnosed with breast cancer in developed countries die from the disease, this proportion reaches over two-thirds in developing countries and is directly related to income per capita (Figure 1a) [1,3]. Berry and colleagues [4] developed a series of independent statistical models of breast cancer incidence in order to determine the relative importance of the contribution of mammographic screening and adjuvant therapy to the marked decline in breast cancer mortality in the majority of developed countries. They estimated the mortality decline was related equally to screening and therapy and that mortality would increase in countries with limited facilities for screening and treatment (Figure 1b).The analyses of Berry and colleagues and trials of screening indicate the importance of early detection by mammography. However, where mammographic screening is introduced into a country gradually, improvements in outcome are also seen in the non-screened group, which may, in part, be related to a general increase in awareness of the importance of early treatment [5,6]. Whilst randomised trials of breast self-examination versus no examination do not demonstrate the effectiveness of the intervention compared with women simply being made aware of breast examination [7], these studies do not address the issue of lack of awareness or of barriers to women presenting early rather than late. In many developing countries, the introduction of mammographic screening is currently not possible because of expense, the relatively low incidence of breast cancer and low age of diagnosis. Thus, the Early Resource Allocation Panel of the Breast Health Global Initiative (BHGI) produced guidelines suggesting a graded system of introduction for breast awareness and mammography based on whether the health care system was basic, limited, enhanced or maximal [8,9]. In countries with basic and limited resources they suggest the widespread introduction of culturally
An early peak of relapse after surgery for breast cancer
Anthony Howell
Breast Cancer Research , 2004, DOI: 10.1186/bcr946
Abstract: The recent research paper by the Milan group reports the time to recurrence after removal of a primary breast tumour in a group of 1173 patients entered into clinical trials in Milan between 1964 and 1980 [1]. All patients were treated by radical or modified radical mastectomy but they did not receive postoperative radiotherapy or chemotherapy. Previous analyses of this patient series estimating the hazard ratio for relapse at 6–12 month intervals reported peaks of relapse at 18 months and 60 months and then a tapered plateau like tail of relapse extending up to 15 years [2]. The early peak was more pronounced in patients with node-positive tumours that were more than 2 cm in diameter. No differences in the curves were seen for local and distant relapse or for pre- and postmenopausal patients. At the same time Saphner and colleagues reported similar findings [3], with the additional observation that the early peak was significantly higher in oestrogen receptor (ER) negative tumours. No ER data are available for the Milan series.In the current paper by the Milan group, the aim of the authors was to further interrogate the kinetics of the first peak. Hazard rates were calculated at three month intervals and the authors report in detail 368 patients with a local (95) or distant (273) relapse within the first four years after surgery. The analysis demonstrates, for the first time, a double peak of early relapse with maximum at 8–10 months and 28–30 months for premenopausal patients, but a wide peak with a maximum at 18–24 months for postmenopausal patients. When divided into node-positive and node-negative, the double pattern was seen only in node-positive premenopausal patients: it was more pronounced in patients with more than three nodes involved, but was unrelated to tumour size.This analysis therefore confirms a previous one in the same group of patients, which showed that 27% of all distant relapses of premenopausal node-positive patients occurred within the first
Can metabolomics in addition to genomics add to prognostic and predictive information in breast cancer?
Anthony Howell
BMC Medicine , 2010, DOI: 10.1186/1741-7015-8-73
Abstract: See research article: http://www.biomedcentral.com/1471-2407/10/628 webciteThe major problems in breast cancer are predicting women at risk more precisely and predicting the presence of micrometastases at the time of primary surgery, including whether they will grow in the future and their responsiveness to systemic therapy. Transcriptomics have led to improvements of standard prognostic markers such as tumour size and axillary lymph node status. In parallel, kits for delineating expression of selected predictive and prognostic gene expression profiles have been developed and are commercially available. Clinical trials (TAYLORX and MINDACT) are in progress to determine their value for selection of appropriate adjuvant systemic hormone and chemotherapy. However, the question arises whether other 'omics' such as proteomics and metabolomics can add to the prognostic and predictive information already available from genomics given the heterogeneity and remaining behavioural unpredictability of breast tumours, as well as whether such studies might indicate additional therapeutic targets or whether adding 'omic' platforms together may be clinically useful? The paper by Borgan et al. [1], published this month in BMC Cancer, from two centres in Norway is the first attempt to assess the interactive value of transcriptomics and metabolomics in a series of primary breast cancers.Metabolomics is the study of the metabolic changes which occur in living systems as a result of gene and protein expression and may enhance the information provided by genomics and proteomics. The metabolome may be the most sensitive measure of cellular phenotype, and methods are evolving to measure the metabolome of a single cell. Analytical methods for metabolomics analysis include liquid chromatography-mass spectroscopy (hundreds of metabolites with multiple unknown peaks), gas chromatography-mass spectroscopy (GC-MS approximately 120 to 200 metabolites) and the method used in the paper by Borgan et
An Introduction to Chaotic dynamical systems. 2nd Edition, by Robert L. Devaney
Garry Howell
International Journal of Stochastic Analysis , 1990, DOI: 10.1155/s1048953390000077
Some Student Teachers’ Conceptions of Creativity in Secondary School English
Beth Howell
English Language Teaching , 2008, DOI: 10.5539/elt.v1n2p36
Abstract: This article explores a group of trainee teachers’ conceptions of Creativity in Secondary School English. Data was collected by means of questionnaires and interviews. Whilst there are many promising notions of creativity, the results also reveal some evidence of narrow conceptions, inconsistent thinking and some misconceptions. This suggests that there may be significant implications for teacher trainers in universities and schools if we are to equip our students with the knowledge, understanding and skills to teach, support and facilitate creativity in their new careers. Romantic notions of original and innate genius, and a progressive emphasis on boundless, directionless play are two possible sources of misconceived ideas for training teachers of English. Creativity can be supported and developed within pedagogical frameworks and settings. This article, therefore, offers a consideration of how Sternberg’s 21 suggested strategies for “Developing creativity as a decision” might be adapted and implemented in the Secondary English classroom. Practical teaching methods and competencies are presented which could be developed and incorporated into graduate trainee teacher programmes.
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