Biomedical subjects

M D Betterton

Publications and source records attributed to M D Betterton.

8 recordsLinked to original sources

PubMed2006

Using the nucleotide substitution rate matrix to detect horizontal gene transfer.

BACKGROUND: Horizontal gene transfer (HGT) has allowed bacteria to evolve many new capabilities. Because transferred genes perform many medically important functions, such as conferring antibiotic resistance, improved detection of horizontally transferred genes from sequence data would be an important advance. Existing sequence-based methods for detecting HGT focus on changes in nucleotide composition or on differences between gene and genome phylogenies; these methods have high error rates. RESULTS: First, we introduce a new class of methods for detecting HGT based on the changes in nucleotide substitution rates that occur when a gene is transferred to a new organism. Our new methods discriminate simulated HGT events with an error rate up to 10 times lower than does GC content. Use of models that are not time-reversible is crucial for detecting HGT. Second, we show that using combinations of multiple predictors of HGT offers substantial improvements over using any single predictor, yielding as much as a factor of 18 improvement in performance (a maximum reduction in error rate from 38% to about 3%). Multiple predictors were combined by using the random forests machine learning algorithm to identify optimal classifiers that separate HGT from non-HGT trees. CONCLUSION: The new class of HGT-detection methods introduced here combines advantages of phylogenetic and compositional HGT-detection techniques. These new techniques offer order-of-magnitude improvements over compositional methods because they are better able to discriminate HGT from non-HGT trees under a wide range of simulated conditions. We also found that combining multiple measures of HGT is essential for detecting a wide range of HGT events. These novel indicators of horizontal transfer will be widely useful in detecting HGT events linked to the evolution of important bacterial traits, such as antibiotic resistance and pathogenicity.

Computational Biology↗

PubMed2006

Controlled irradiative formation of penitentes.

Spike-shaped structures are produced by light-driven ablation in very different contexts. Penitentes 1-4 m high are common on Andean glaciers, where their formation changes glacier dynamics and hydrology. Laser ablation can produce cones 10-100 microm high with a variety of proposed applications in materials science. We report the first laboratory generation of centimeter-scale snow and ice penitentes. Systematically varying conditions allows identification of the parameters controlling the formation of ablation structures. We demonstrate that penitente initiation and coarsening require cold temperatures, so that ablation leads to sublimation. Once penitentes have formed, further growth of height can occur by melting. The penitentes initially appear as small structures (3 mm high) and grow by coarsening to 1-5 cm high. Our results are an important step towards understanding ablation morphologies.

Journal Article↗

PubMed2006

Systems theory of Smad signalling.

Transforming growth factor-beta (TGFbeta) signalling is an important regulator of cellular growth and differentiation. The principal intracellular mediators of TGFbeta signalling are the Smad proteins, which upon TGFbeta stimulation accumulate in the nucleus and regulate the transcription of target genes. To investigate the mechanisms of Smad nuclear accumulation, we developed a simple mathematical model of canonical Smad signalling. The model was built using both published data and our experimentally determined cellular Smad concentrations (isoforms 2, 3 and 4). We found in mink lung epithelial cells that Smad2 (8.5-12 x 10(4) molecules cell(-1)) was present in similar amounts to Smad4 (9.3-12 x 10(4) molecules cell(-1)), whereas both were in excess of Smad3 (1.1-2.0 x 10(4) molecules cell(-1)). Variation of the model parameters and statistical analysis showed that Smad nuclear accumulation is most sensitive to parameters affecting the rates of R-Smad phosphorylation and dephosphorylation and Smad complex formation/ dissociation in the nucleus. Deleting Smad4 from the model revealed that rate-limiting phospho-R-Smad dephosphorylation could be an important mechanism for Smad nuclear accumulation. Furthermore, we observed that binding factors constitutively localised to the nucleus do not efficiently mediate Smad nuclear accumulation, if dephosphorylation is rapid. We therefore conclude that an imbalance in the rates of R-Smad phosphorylation and dephosphorylation is likely an important mechanism of Smad nuclear accumulation during TGFbeta signalling.

Animals↗

PubMed2005

Incorporating expression data in metabolic modeling: a case study of lactate dehydrogenase.

Integrating biological information from different sources to understand cellular processes is an important problem in systems biology. We use data from mRNA expression arrays and chemical kinetics to formulate a metabolic model relevant to K562 erythroleukemia cells. MAP kinase pathway activation alters the expression of metabolic enzymes in K562 cells. Our array data show changes in expression of lactate dehydrogenase (LDH) isoforms after treatment with phorbol 12-myristate 13-acetate (PMA), which activates MAP kinase signaling. We model the change in lactate production which occurs when the MAP kinase pathway is activated, using a non-equilibrium, chemical-kinetic model of homolactic fermentation. In particular, we examine the role of LDH isoforms, which catalyse the conversion of pyruvate to lactate. Changes in the isoform ratio are not the primary determinant of the production of lactate. Rather, the total concentration of LDH controls the lactate concentration.

Cell Line, Tumor↗

PubMed2005

Opening of nucleic-acid double strands by helicases: active versus passive opening.

Helicase proteins move along double-stranded nucleic-acid molecules and unwind the double helix. This paper presents a theoretical study of the coupling between helicase translocation and duplex unwinding. Two different cases-active and passive opening-are usually distinguished. In active opening, the helicase directly destabilizes the double-stranded nucleic acid (dsNA) to promote opening. Passive opening implies that the helicase binds ssNA available when a thermal fluctuation partially opens the dsNA. We formulate a discrete model for helicase motion. An interaction potential describes how the helicase affects duplex unwinding when near a junction between single-stranded and double-stranded NA. Different choices of the potential correspond to the cases of active and passive opening. An optimal choice of interaction potential leads to a helicase which can unwind NA as rapidly as it translocates on single strands.

Binding Sites↗

PubMed2003

A motor that makes its own track: helicase unwinding of DNA.

We study the unwinding of DNA by helicase proteins as a representative system in which a motor protein interacts with a mobile obstacle. In our discrete model, the interaction between the helicase and the DNA fork is characterized by an interaction potential. For the case of a hard-wall potential, the helicase opens the DNA by rectifying thermal fluctuations which spontaneously open base pairs. A potential with nonzero range describes the destabilization of the double strand by the enzymatic action of the helicase. We derive solutions for the opening speed as a function of the potential shape and relate our results to experiments on helicase motion.

DNA↗

PubMed2001

Collapsing bacterial cylinders.

Under special conditions bacteria excrete an attractant and aggregate. The high density regions initially collapse into cylindrical structures, which subsequently destabilize and break up into spherical aggregates. This paper presents a theoretical description of the process, from the structure of the collapsing cylinder to the spacing of the final aggregates. We show that cylindrical collapse involves a delicate balance in which bacterial attraction and diffusion nearly cancel, leading to corrections to the collapse laws expected from dimensional analysis. The instability of a collapsing cylinder is composed of two distinct stages: Initially, slow modulations to the cylinder develop, which correspond to a variation of the collapse time along the cylinder axis. Ultimately, one point on the cylinder pinches off. At this final stage of the instability, a front propagates from the pinch into the remainder of the cylinder. The spacing of the resulting spherical aggregates is determined by the front propagation.

Bacterial Physiological Phenomena↗

PubMed2001

Theory of structure formation in snowfields motivated by penitentes, suncups, and dirt cones.

Penitentes and suncups are structures formed as snow melts, typically high in the mountains. When the snow is dirty, dirt cones and other structures can form instead. Building on previous field observations and experiments, this paper presents a theory of ablation morphologies, and the role of surface dirt in determining the structures formed. The glaciological literature indicates that sunlight, heating from air, and dirt all play a role in the formation of structure on an ablating snow surface. The present paper formulates a minimal model for the formation of ablation morphologies as a function of measurable parameters and considers the linear stability of this model. The dependence of ablation morphologies on weather conditions and initial dirt thickness is studied, focusing on the initial growth of perturbations away from a flat surface. We derive a single-parameter expression for the melting rate as a function of dirt thickness, which agrees well with a set of measurements by Driedger. An interesting result is the prediction of a dirt-induced traveling instability for a range of parameters.

Journal Article↗