Biomedical subjects

M S Turner

Publications and source records attributed to M S Turner.

At least 19 recordsLinked to original sources

PubMed2006

Stall, spiculate, or run away: The fate of fibers growing towards fluctuating membranes.

We study the dynamics of a growing semiflexible fiber approaching a membrane at an angle. At late times we find three regimes: fiber stalling, when growth stops, runaway, in which the fiber bends away from the membrane, and another regime in which spicules form. We discuss which regions of the resulting "phase diagram" are explored by (i) single and bundled actin fibers in living cells, (ii) sickle hemoglobin fibers, and (iii) microtubules inside vesicles. We complement our analysis with 3D stochastic simulations.

Actin Cytoskeleton↗

PubMed2006

Fiber depolymerization.

Depolymerization is, by definition, a crucial process in the reversible assembly of various biopolymers. It may also be an important factor in the pathology of sickle cell disease. If sickle hemoglobin fibers fail to depolymerize fully during passage through the lungs then they will reintroduce aggregates into the systemic circulation and eliminate or shorten the protective delay (nucleation) time for the subsequent growth of fibers. We study how depolymerization depends on the rates of end- and side-depolymerization, k(end) and k(side), which are, respectively, the rates at which fiber length is lost at each end and the rate at which new breaks appear per unit fiber length. We present both an analytic mean field theory and supporting simulations showing that the characteristic fiber depolymerization time tau= square root 1/k(end)k(side) depends on both rates, but not on the fiber length L, in a large intermediate regime 1 << k(side)L(2)/k(end) << (L/d)(2), with d the fiber diameter. We present new experimental data which confirms that both mechanisms are important and shows how the rate of side depolymerization depends strongly on the concentration of CO, acting as a proxy for oxygen. Our theory remains rather general and could be applied to the depolymerization of an entire class of linear aggregates, not just sickle hemoglobin fibers.

Carbon Monoxide↗

PubMed2006

Anisotropy in sickle hemoglobin fibers from variations in bending and twist.

We have studied the variations of twist and bend in sickle hemoglobin fibers. We find that these variations are consistent with an origin in equilibrium thermal fluctuations, which allows us to estimate the bending and torsional rigidities and effective corresponding material moduli. We measure bending by electron microscopy of frozen hydrated fibers and find that the bending persistence length, a measure of the length of fiber required before it starts to be significantly bent due to thermal fluctuations, is 130microm, somewhat shorter than that previously reported using light microscopy. The torsional persistence length, obtained by re-analysis of previously published experiments, is found to be only 2.5microm. Strikingly this means that the corresponding torsional rigidity of the fibers is only 6x10(-27)Jm, much less than their bending rigidity of 5x10(-25)Jm. For (normal) isotropic materials, one would instead expect these to be similar. Thus, we present the first quantitative evidence of a very significant material anisotropy in sickle hemoglobin fibers, as might arise from the difference between axial and lateral contacts within the fiber. We suggest that the relative softness of the fiber with respect to twist deformation contributes to the metastability of HbS fibers: HbS double strands are twisted in the fiber but not in the equilibrium crystalline state. Our measurements inform a theoretical model of the thermodynamic stability of fibers that takes account of both bending and extension/compression of hemoglobin (double) strands within the fiber.

Anisotropy↗

PubMed2006

Deforming biological membranes: how the cytoskeleton affects a polymerizing fiber.

We give a theoretical treatment of the force exerted by a fluctuating membrane on a polymer rod tip, taking into account the effects of an underlying biological cytoskeleton by way of a simple harmonic dependence on displacement. We also consider theoretically and experimentally the dynamics of a growing fiber tip under the influence of such a fluctuation-induced membrane force, including the effects of an underlying cytoskeletal network. We compare our model with new experimental data for the growth of hemoglobin fibers within red blood cells, revealing a good agreement. We are also able to estimate the force and membrane/cytoskeletal displacement required to stall growth of, or buckle, a growing fiber. We discuss the significance of our results in a biological context, including how the properties of the membrane and cytoskeleton relate to the thermodynamics of rod polymerization.

Biophysics↗

PubMed2005

Spicules and the effect of rigid rods on enclosing membrane tubes.

Membrane tubes (spicules) arise in cells, or artificial membranes, in the nonlinear deformation regime due to, e.g., the growth of microtubules, actin filaments, or sickle hemoglobin fibers towards a membrane. We calculate the axial force f exerted by the tube, and its average radius, taking into account steric interactions between the fluctuating membrane and the enclosed rod. We find a smooth crossover of the axial force between f approximately square root of (sigma) and f approximately sigma as the membrane tension sigma increases and the tube radius shrinks. This crossover occurs around the most physiologically relevant membrane tensions. Our work may be important in (i) interpreting experiments in which axial force is related to the tube radius or membrane tension, and (ii) constructing dynamical theories for biopolymer growth in narrow tubes where these fluctuation effects control the tube radius.

Cell Surface Extensions↗

PubMed2005

Modelling genetic networks with noisy and varied experimental data: the circadian clock in Arabidopsis thaliana.

Circadian clocks in all organisms include feedback loops that generate rhythmic expression of key genes. We model the first such loop proposed for the clock of Arabidopsis thaliana, the experimental model species for circadian timing in higher plants. As for many biological systems, there are no experimental values for the parameters in our model, and the data available for parameter fitting is noisy and varied. To tackle this we constructed a cost function, which quantifies the agreement between our model and various key experimental features. We then undertook an efficient global search of parameter space, to test whether the proposed circuit can fit the experimental data. Using this approach we show that circadian clock models can function well with low cooperativity in transcriptional regulation, whereas high cooperativity has been a feature of previous (hand-fitted) clock models in other species. Our optimized solution for the Arabidopsis clock model fits several, but not all, of the key experimental features. We test the predicted effects of well-characterized mutations in the clock circuit and show the phases of the circadian cycle where additional components that are yet to be identified experimentally must be present to complete the circadian feedback loop.

Arabidopsis↗

PubMed2005

Measuring forces between protein fibers by microscopy.

We propose a general scheme for measuring the attraction between mechanically frustrated semiflexible fibers by measuring their thermal fluctuations and shape. We apply this analysis to a system of sickle hemoglobin (HbS) fibers that laterally attract one another. These fibers appear to "zip" together before reaching mechanical equilibrium due to the existence of cross-links into a dilute fiber network. We are also able to estimate the rigidities of the fibers. These rigidities are found to be consistent with sickle hemoglobin "single" fibers 20 nm in diameter, despite recent experiments indicating that fiber bundling sometimes occurs. Our estimate of the magnitude of the interfiber attraction for HbS fibers is in the range 8 +/- 7 kBT/microm, or 4 +/- 3 k(B)T/microm if the fibers are assumed, a priori to be single fibers (such an assumption is fully consistent with the data). This value is sufficient to bind the fibers, overcoming entropic effects, although extremely chemically weak. Our results are compared to models for the interfiber attraction that include depletion and van der Waals forces. This technique should also facilitate a similar analysis of other filamentous protein assembles in the future, including beta-amyloid, actin, and tubulin.

Biophysics↗

PubMed2004

The force generated by biological membranes on a polymer rod and its response: statics and dynamics.

We propose a theory for the force exerted by a fluctuating membrane on a polymer rod tip. Using statistical mechanical methods, the expression for the generated force is written in terms of the distance of the rod tip from the membrane "frame." We apply the theory in calculating the stall force and membrane displacement required to cease the growth of a growing fiber induced by membrane fluctuations, as well as the membrane force and membrane displacement required for rod/fiber buckling. We also consider the dynamics of a growing fiber tip under the influence of a fluctuation-induced membrane force. We discuss the importance of our results in various biological contexts. Finally, we present a method to simultaneously extract both the rigidity of the semiflexible rod and the force applied by, e.g., the membrane from the measurements of the bending fluctuations of the rod. Such a measurement of the force would give information about the thermodynamics of the rod polymerization that involves the usual Brownian ratchet mechanism.

Anisotropy↗

PubMed2004

Left ventricular pacing minimizes diastolic ventricular interaction, allowing improved preload-dependent systolic performance.

BACKGROUND: Left ventricular (LV) pacing improves hemodynamics in patients with heart failure. We hypothesized that at least part of this benefit occurs by minimization of external constraint to LV filling from ventricular interaction. METHODS AND RESULTS: We present median values (interquartile ranges) for 13 heart failure patients with LV pacing systems implanted for New York Heart Association class III/IV limitation. We used the conductance catheter method to measure LV pressure and volume simultaneously. External constraint was measured from the end-diastolic pressure-volume relation recorded during inferior vena caval occlusion, during LV pacing, and while pacing was suspended. External constraint to LV filling was reduced by 3.0 (4.6 to 0.6) mm Hg from 4.8 (0.6 to 7.5) mm Hg (P<0.01) in response to LV pacing; effective filling pressure (LV end-diastolic pressure minus external constraint) increased by 4.0 (2.2 to 5.8) mm Hg from 17.7 (13.3 to 22.6; P<0.01). LV end-diastolic volume increased by 10 (3 to 11) mL from 238 (169 to 295) mL (P=0.01), whereas LV end-systolic volume did not change significantly (-1 [-2 to 3] mL from 180 [124 to 236] mL, P=0.97), which resulted in an increase in stroke volume of 11 (5 to 13) mL from 49 (38 to 59) mL (P<0.01). LV stroke work increased by 720 (550 to 1180) mL . mm Hg from 3400 (2110 to 4480) mL . mm Hg (P=0.01), and maximum dP/dt increased by 120 (2 to 161) mm Hg/s from 635 (521 to 767) mm Hg/s (P=0.03). CONCLUSIONS: This study suggests a potentially important mechanism by which LV pacing may produce hemodynamic benefit. LV pacing minimizes external constraint to LV filling, resulting in an increase in effective filling pressure; the consequent increase in LV end-diastolic volume increases stroke volume via the Starling mechanism.

Aged↗

PubMed2004

The wild-type circadian period of Neurospora is encoded in the residual network of the null frq mutants.

We model theoretically the response of the widely studied circadian oscillator of Neurospora crassa to inactivation of the frq gene. The resulting organism has been termed "arrhythmic" under constant conditions. Under entrainment to periodic temperature cycles Roenneberg, Merrow and coworkers have shown that the phase angle at which spore formation occurs depends on the entrainment period, curiously even in the null frq mutants (frq9 and frq10). We show that such a response does not imply the presence of a self-sustained free-running oscillator. We derive a simple candidate model (a damped harmonic oscillator) for the null frq mutants that successfully reproduces the observed phase angle response. An endogenous period of 21 h for the damped harmonic oscillator coincides with the endogenous period of wild-type Neurospora. This suggests that the (noise driven) "residual system" present in the mutants may have a significant timekeeping role in the wild-type organism. Our model (with no change of parameters) was then used to investigate spore formation patterns under constant conditions and reproduces the corresponding experimental data of Aronson et al. (Proc. Natl. Acad. Sci. USA 91 (1994) 7683.)

Biological Clocks↗

PubMed2004

Left ventricular pacing improves haemodynamic variables in patients with heart failure with a normal QRS duration.

OBJECTIVES: To assess whether patients with congestive heart failure (CHF) and a normal QRS duration can benefit from left ventricular (VDD-LV) pacing. DESIGN: Cardiac resynchronisation is reserved for patients with a broad QRS duration on the premise that systolic resynchronisation is the mechanism of benefit, yet improvement from pacing correlates poorly with QRS duration. In CHF patients with a broad QRS duration, those with a high resting pulmonary capillary wedge pressure (PCWP) > 15 mm Hg benefit. In this acute haemodynamic VDD-LV pacing study, patients with CHF with a normal QRS duration were divided into two groups--patients with a resting PCWP > 15 mm Hg and patients with a resting PCWP < 15 mm Hg--to determine whether benefit is predicted by a high resting PCWP. PATIENTS: 20 patients with CHF, New York Heart Association functional class IIb-IV, all with a normal QRS duration (< or = 120 ms). INTERVENTIONS: Temporary pacing wires were positioned to enable VDD-LV pacing and a pulmonary artery catheter was inserted for measurement of PCWP, right atrial pressure, and cardiac output. RESULTS: In patients with a PCWP > 15 mm Hg (n = 10), cardiac output increased from 3.9 (1.5) to 4.5 (1.65) l/min (p < 0.01), despite a fall in PCWP from 24.7 (7.1) to 21.0 (6.2) mm Hg (p < 0.001). In patients with a PCWP < 15 mm Hg there was no change in PCWP or cardiac output. Combined data showed that PCWP decreased from 17.0 (9.1) to 15.3 (7.7) mm Hg during VDD-LV pacing (p < 0.014) and cardiac output increased non-significantly from 4.7 (1.5) to 4.9 (1.5) (p = 0.125). CONCLUSIONS: Patients with CHF with a normal QRS duration and PCWP > 15 mm Hg derive acute haemodynamic benefit from VDD-LV pacing.

Cardiac Output↗

PubMed2004

Possible therapeutic targets in cardiac myocyte apoptosis.

Since Kerr described programmed cell death (apoptosis) as a process distinct from necrosis, there have been many studies of apoptosis in disease, especially of immunological origin. Because cardiac myocytes are terminally differentiated cells, they have typically been assumed to die exclusively by necrosis. However, during the last decade this view has been challenged by several studies demonstrating that a significant number of cardiac myocytes undergo apoptosis in myocardial infarction, heart failure, myocarditis, arrhythmogenic right ventricular dysplasia, and immune rejection after cardiac transplantation, as well as in other conditions of stress. These are potentially relevant observations, because apoptosis--unlike necrosis--can be blocked or reversed at early stages. Specific inhibition of this process may confer a considerable degree of cardioprotection, but requires a thorough understanding of the underlying mechanisms. Recent progress includes a better understanding of the importance of mitochondria-initiated events in cardiac myocyte apoptosis, of factors inducing apoptosis in heart failure and during hypoxia, and of the dual pro-apoptotic and anti-apoptotic effects of hypertrophic stimuli such as beta-adrenoceptor agonists, angiotensin converting enzyme inhibitors, nitric oxide and calcineurin. The investigation of cytoprotective and apoptotic signal transduction pathways has revealed important new insights into the roles of the mitogen-activated protein kinases p38, extracellular signal regulated kinase and c-Jun N-terminal kinase in cardiac cell fate. Our present review focuses on the intracellular signal transduction pathways of cardiac myocyte apoptosis and the possibility of specific inhibition of the process.

Animals↗

PubMed2003

Interactions between proteins bound to biomembranes.

We study a physical model for the interaction between general inclusions bound to fluid membranes that possess finite tension gamma, as well as the usual bending rigidity kappa. We are motivated by an interest in proteins bound to cell membranes that apply forces to these membranes, due to either entropic or direct chemical interactions. We find an exact analytic solution for the repulsive interaction between two similar circularly symmetric inclusions. This repulsion extends over length scales approximately sqrt[kappa/gamma] and contrasts with the membrane-mediated contact attraction for similar inclusions on tensionless membranes. For noncircularly symmetric inclusions we study the small, algebraically long-ranged, attractive contribution to the force that arises. We discuss the relevance of our results to biological phenomena, such as the budding of caveolae from cell membranes and the striations that are observed on their coats. These, and other, "gnarly buds" may prove fascinating to study further.

Biophysical Phenomena↗

PubMed2003

Twisted protein aggregates and disease: the stability of sickle hemoglobin fibers.

We describe how twist could play an essential role in stabilizing 20 nm diameter sickle hemoglobin fibers. Our theory successfully reproduces the observed variation of helical pitch length with fiber diameter. With no remaining adjustable parameters it also yields a prediction for the torsional rigidity of sickle hemoglobin fibers that is in good agreement with experiment and hence retains the striking feature that such fibers can be highly mechanically anisotropic, even with a ratio of bending to torsional rigidity of about 50. We discuss how our study might be relevant to the development of treatment strategies.

Hemoglobin, Sickle↗

PubMed2003

Early use of intrathecal baclofen in brain injury in pediatric patients.

BACKGROUND: The Food and Drug Administration (FDA) approved the use of intrathecal Baclofen for spasticity from traumatic brain injury in June of 1996 based on a Phase III clinical trial that documented efficacy in patients one year post injury. The FDA approval is only for patients who are one year post injury based on the Phase III study. We have found use of ITB in the first few months after injury very effective in a subgroup of severe traumatic brain injury (TBI) pediatric patients with spasticity, dystonia and autonomic storming following brain injury. METHOD: The author's database of over 250 patients receiving intrathecal baclofen was reviewed. Retrospective chart review was undertaken of the 6 patients identified with brain injuries over a three year period that were given ITB less than one year post injury. The patients' diagnosis included asphyxia, traumatic brain injury and stroke. The ages were one year to fourteen years of age. ITB was offered after all conventional therapy had been exhausted and the patient's spasticity remained intractable. These patients also all experienced autonomic dysfunction with severe autonomic storms. FINDINGS: All of the patients had a decrease in their spasticity of at least 2 points on the Ashworth score. The autonomic storms ceased in all 6 patients when adequate dosages of ITB were reached. The patients could be weaned from all oral and intravenous medications for tone, storming and fever. Many of the patients became much more alert and interactive when the medications were stopped. Five of the six are still using their pump for their tone one to five years post implant, the sixth had the pump stopped at the parents' request for religious reasons. INTERPRETATION: Early use of ITB can play a significant role in the rehabilitation of brain injury in children.

Adolescent↗

PubMed2003

Intrathecal drug delivery 2002.

BACKGROUND: Intrathecal drug delivery has been used clinically since the 1970's. Significant clinical advances have been made combining new technology with pharmacology and surgery. Continuous infusion of medication for both analgesia and spasticity has become a part of the armamentarium for specialists in these areas. Significant recent advances in technology promise further enhancements and improvements for intrathecal therapy. METHODS: A review of the literature combined with 20 years personal experience with intrathecal drug delivery. FINDINGS/DISCUSSION: Intrathecal therapy has established a role in the treatment of malignant pain, benign pain and severe spasticity. Significant literature and the current state of practice in the United States are reviewed. Recent therapeutic enhancements are discussed, and a wish list of future technological enhancements presented.

Baclofen↗

PubMed2001

Regulation of limbic information outflow by the subthalamic nucleus: excitatory amino acid projections to the ventral pallidum.

The subthalamic nucleus (STN), a component of the basal ganglia motor system, sends an excitatory amino acid (EAA)-containing projection to the ventral pallidum (VP), a major limbic system output region. The VP contains both NMDA and AMPA subtypes of EAA receptors. To characterize the physiology of the subthalamic pathway to the VP, and to determine the influence of EAA receptor subtypes, in vivo intracellular recordings, and in vivo extracellular recordings combined with microiontophoresis, were made from VP neurons in anesthetized rats. Of the intracellularly recorded neurons, 86% responded to STN stimulation, and these displayed EPSPs with an onset of 8.7 msec, consistent with a monosynaptic input. The EPSPs evoked in spontaneously firing neurons were nearly twice the amplitude of those in nonfiring cells (13.1 vs 6.8 mV, respectively). As neurons were depolarized by current injection, the latency for spiking decreased from 24.2 to 14.2 msec, although EPSP latency was unaffected. Eighty-seven percent of the extracellularly recorded VP neurons responded to STN stimulation with a rapid and robust enhancement of spiking; the response onset, like the EPSP onset, equaled 8.7 msec. Firing rate was enhanced by NMDA in 94% of the STN-excited cells, and AMPA increased firing in 94% as well. The NMDA-selective antagonist AP-5 attenuated 67% of the STN-evoked excitatory responses, and the AMPA-selective antagonist CNQX attenuated 52%. Both antagonists attenuated 33% of responses, and 78% were attenuated by at least one. This evidence suggests that a great majority of VP neurons are directly influenced by STN activation and that both NMDA and non-NMDA receptors are involved. Moreover, the VP response to STN stimulation appears to be strongly dependent on the depolarization state of the neuron.

Action Potentials↗

PubMed2001

Precision cosmology and the density of baryons in the universe.

Big-bang nucleosynthesis (BBN) and cosmic microwave background (CMB) anisotropy measurements give independent, accurate measurements of the baryon density and can test the framework of the standard cosmology. Early CMB data are consistent with the long-standing conclusion from BBN that baryons constitute a small fraction of matter in the Universe, but may indicate a slightly higher value for the baryon density. We clarify precisely what the two methods determine and point out that differing values for the baryon density can indicate either an inconsistency or physics beyond the standard models of cosmology and particle physics. We discuss other signatures of the new physics in CMB anisotropy.

Journal Article↗