Biomedical subjects

Matthew S Turner

Publications and source records attributed to Matthew S Turner.

12 recordsLinked to original sources

PubMed2006

Experimental validation of a predicted feedback loop in the multi-oscillator clock of Arabidopsis thaliana.

Our computational model of the circadian clock comprised the feedback loop between LATE ELONGATED HYPOCOTYL (LHY), CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) and TIMING OF CAB EXPRESSION 1 (TOC1), and a predicted, interlocking feedback loop involving TOC1 and a hypothetical component Y. Experiments based on model predictions suggested GIGANTEA (GI) as a candidate for Y. We now extend the model to include a recently demonstrated feedback loop between the TOC1 homologues PSEUDO-RESPONSE REGULATOR 7 (PRR7), PRR9 and LHY and CCA1. This three-loop network explains the rhythmic phenotype of toc1 mutant alleles. Model predictions fit closely to new data on the gi;lhy;cca1 mutant, which confirm that GI is a major contributor to Y function. Analysis of the three-loop network suggests that the plant clock consists of morning and evening oscillators, coupled intracellularly, which may be analogous to coupled, morning and evening clock cells in Drosophila and the mouse.

Arabidopsis↗

PubMed2006

A kinetic model describing the processivity of myosin-V.

The precise details of how myosin-V coordinates the biochemical reactions and mechanical motions of its two head elements to engineer effective processive molecular motion along actin filaments remain unresolved. We compare a quantitative kinetic model of the myosin-V walk, consisting of five basic states augmented by two further states to allow for futile hydrolysis and detachments, with experimental results for run lengths, velocities, and dwell times and their dependence on bulk nucleotide concentrations and external loads in both directions. The model reveals how myosin-V can use the internal strain in the molecule to synchronize the motion of the head elements. Estimates for the rate constants in the reaction cycle and the internal strain energy are obtained by a computational comparison scheme involving an extensive exploration of the large parameter space. This scheme exploits the fact that we have obtained analytic results for our reaction network, e.g., for the velocity but also the run length, diffusion constant, and fraction of backward steps. The agreement with experiment is often reasonable but some open problems are highlighted, in particular the inability of such a general model to reproduce the reported dependence of run length on ADP concentration. The novel way that our approach explores parameter space means that any confirmed discrepancies should give new insights into the reaction network model.

Actin Cytoskeleton↗

PubMed2006

Budded membrane microdomains as tension regulators.

We propose a mechanism by which changes of the mechanical tension of a composite lipid membrane are buffered by the invagination of membrane domains. We show that domain invagination, driven by differences in chemical composition, is a first-order transition controlled by membrane tension. The invaginated domains play the role of a membrane reservoir, exchanging area with the main membrane, and impose an equilibrium tension entirely controlled by their mechanical properties. The dynamical response of the reservoir reflects the tension-dependent kinetics of the domain shape transition, so that the tension of such a composite membrane is inherently transient and dynamical. The implications of this phenomenon for the mechanical properties of the membranes of living cells, where invaginated membrane domains are known to exist, are discussed.

Computer Simulation↗

PubMed2005

Nonequilibrium raftlike membrane domains under continuous recycling.

We present a model for the kinetics of spontaneous membrane domain (raft) assembly that includes the effect of membrane recycling ubiquitous in living cells. We show that domains can have a broad power-law distribution with an average radius that scales with the 1/4 power of the domain lifetime when the line tension at the domain edges is large. For biologically reasonable recycling and diffusion rates, the average domain radius is in the tens of nm range, consistent with observations. This represents one possible link between signaling (involving rafts) and traffic (recycling) in cells. Finally, we present evidence that suggests that the average raft size may be the same for all scale-free recycling schemes.

Journal Article↗

PubMed2005

Electronic transport in DNA.

We study the electronic properties of DNA by way of a tight-binding model applied to four particular DNA sequences. The charge transfer properties are presented in terms of localization lengths (crudely speaking, the length over which electrons travel). Various types of disorder, including random potentials, are employed to account for different real environments. We have performed calculations on poly(dG)-poly(dC), telomeric-DNA, random-ATGC DNA, and lambda-DNA. We find that random and lambda-DNA have localization lengths allowing for electron motion among a few dozen basepairs only. A novel enhancement of localization lengths is observed at particular energies for an increasing binary backbone disorder. We comment on the possible biological relevance of sequence-dependent charge transfer in DNA.

Base Sequence↗

PubMed2005

Extension of a genetic network model by iterative experimentation and mathematical analysis.

Circadian clocks involve feedback loops that generate rhythmic expression of key genes. Molecular genetic studies in the higher plant Arabidopsis thaliana have revealed a complex clock network. The first part of the network to be identified, a transcriptional feedback loop comprising TIMING OF CAB EXPRESSION 1 (TOC1), LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), fails to account for significant experimental data. We develop an extended model that is based upon a wider range of data and accurately predicts additional experimental results. The model comprises interlocking feedback loops comparable to those identified experimentally in other circadian systems. We propose that each loop receives input signals from light, and that each loop includes a hypothetical component that had not been explicitly identified. Analysis of the model predicted the properties of these components, including an acute light induction at dawn that is rapidly repressed by LHY and CCA1. We found this unexpected regulation in RNA levels of the evening-expressed gene GIGANTEA (GI), supporting our proposed network and making GI a strong candidate for this component.

Arabidopsis↗

PubMed2005

High-pressure paint-gun injury of the finger simulating giant cell tumor of tendon sheath.

High-pressure paint guns deliver paint at approximately 3000 pounds per square inch. At this pressure, paint will penetrate the skin and spread quickly through fascial planes and tendon sheaths. The present case is that of a lesion from the finger of a 35-year-old white male in whom a history was initially unavailable. Histologic examination revealed diffuse fibrohistiocytic proliferation and giant cells, with numerous darkly pigmented, uniformly small-sized particles throughout the lesion. The initial impression was that of a giant cell tumor of tendon sheath. However, the pigment particles were negative for Perls stain, and polariscopic examination revealed clear refractile fragments. These findings raised the possibility that the lesion was the result of a traumatic event. On further inquiry, it was revealed that the patient had sustained a high-pressure paint-gun injury 1 year earlier. The simulation, histopathologically, of a giant cell tumor of tendon sheath by a high-pressure paint-gun injury has not, to our knowledge, been reported previously, nor has the histologic finding of small, uniformly sized pigment particles and polarizable refractile fragments in this particular type of injury.

Adult↗

PubMed2004

Gating-by-tilt of mechanically sensitive membrane channels.

We propose an alternative mechanism for the gating of biological membrane channels in response to membrane tension that involves a change in the slope of the membrane near the channel. Under biological membrane tensions we show that the energy difference between the closed (tilted) and open (untilted) states can far exceed k(B)T and is comparable to what is available under simple dilational gating. Recent experiments demonstrate that membrane leaflet asymmetries (spontaneous curvature) can strongly affect the gating of some channels. Such a phenomenon would be easier to explain under gating-by-tilt, given its novel intrinsic sensitivity to such asymmetry.

Cell Membrane↗

PubMed2004

Theoretical model for the formation of caveolae and similar membrane invaginations.

We study a physical model for the formation of bud-like invaginations on fluid lipid membranes under tension, and apply this model to caveolae formation. We demonstrate that budding can be driven by membrane-bound proteins, provided that they exert asymmetric forces on the membrane that give rise to bending moments. In particular, caveolae formation does not necessarily require forces to be applied by the cytoskeleton. Our theoretical model is able to explain several features observed experimentally in caveolae, where proteins in the caveolin family are known to play a crucial role in the formation of caveolae buds. These include 1), the formation of caveolae buds with sizes in the 100-nm range and 2), that certain N- and C-termini deletion mutants result in vesicles that are an order-of-magnitude larger. Finally, we discuss the possible origin of the morphological striations that are observed on the surfaces of the caveolae.

Animals↗

PubMed2003

Interactions between sickle hemoglobin fibers.

We report on observations of "zippering" that occurs when two sickle hemoglobin fibers come together side by side. A transient Y-shaped object is formed which "zips " closed. We have been able to show how the strength of the interactions that drive this may be estimated by studying the frustrated structures sometimes formed between several fibers. Our measurements, when combined with mechanical constants determined by an analysis of bending fluctuations, allow us to make the first estimate of the magnitude of these interactions, of the order of 7kBT microm(-1). Hemoglobin volume fractions of tens of %, lead to significant depletion forces. We estimate the magnitude of both the depletion and Van der Waals forces between pairs of single fibers. We study how these are effected by the helical nature of the fibers and renormalised by bending fluctuations, calculations that could have wider applications beyond sickle hemoglobin fibers. Our theoretical analysis of single fibers is in encouraging, although not fully quantitative, agreement with our measurements. We conclude that the physics and rheology of the hemoglobin gel, as well as the pathology of sickle cell anemia itself, may be influenced by depletion interactions.

Algorithms↗

PubMed2003

Stun gun injuries in the abuse and death of a seven-month-old infant.

The author autopsied a seven-month-old infant who was shocked repeatedly with a stun gun by his foster mother, in an attempt by the foster mother to get the infant to stop crying. The stun gun injuries were round, well-circumscribed, erythematous macular lesions, which were found in pairs. The lesions were 2 in. apart, and were found to match the distance between the electrodes of the stun gun found in the foster mother's purse. Based on the electrical output of the stun gun, the small size of the infant, location of stun gun discharge, and the decreased resistance of the infant's skin, it can be concluded that the stun gun injury is responsible for the infant's death.

Child Abuse↗

PubMed2002

Micromechanics of isolated sickle cell hemoglobin fibers: bending moduli and persistence lengths.

Pathogenesis in sickle cell disease depends on polymerization of deoxyhemoglobin S into rod-like fibers, forming gels that rigidify red cells and obstruct the systemic microvasculature. Fiber structure, polymerization kinetics and equilibria are well characterized and intimately related to pathogenesis. However, data on gel rheology, the immediate cause of obstruction, are limited, and models for structure and rheology are lacking. The basis of gel rheology, micromechanics of individual fibers, has never been examined. Here, we isolate fibers by selective depolymerization of gels produced under photolytic deliganding of CO hemoglobin S. Using differential interference contrast (DIC) microscopy, we measure spontaneous, thermal fluctuations in fiber shape to obtain bending moduli (kappa) and persistence lengths (lambda(p)). Some fibers being too stiff to decompose shape accurately into Fourier modes, we measure deviations of fiber midpoints from mean positions. Serial deviations, sufficiently separated to be independent, exhibit Gaussian distributions and provide mean-squared fluctuation amplitudes from which kappa and lambda(p) can be calculated. Lambda(p) ranges from 0.24 to 13 mm for the most flexible and stiffest fibers, respectively. This large range reflects formation of fiber bundles. If the most flexible are single fibers, then lambda(p) =13 mm represents a bundle of seven single fibers. Preliminary data on the bending variations of frozen, hydrated single fibers of HbS obtained by electron microscopy indicate that the value 0.24 mm is consistent with the persistence length of single fibers. Young's modulus is 0.10 GPa, less than for structural proteins but much larger than for extensible proteins. We consider how these results, used with models for cross-linking, may apply to macroscopic rheology of hemoglobin S gels. This new technique, combining isolation of hemoglobin S fibers and measurement of micromechanical properties based on thermal fluctuations and midpoint deviations, can be used to study fibers of mutants, hemoglobin A/S, and mixtures and hybrids of hemoglobin S.

Anemia, Sickle Cell↗