Dissertations / Theses on the topic 'Animal physiology - biophysics'
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1
Ferreira, Matos Gomes Rute. "Respiratory mechanics in small animals : influence of size and age." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=38188.
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Although rodents have been widely used in respiratory research, there are still only limited data comparing respiratory mechanics between different species of small animal. In order to provide further insight into the mechanical behavior of the respiratory systems of different sized small animals, accurate measurements of respiratory impedance (Zrs) were made in four different rodent species and in the developing rat over a broad range of frequencies at various levels of positive end-expiratory pressure (PEEP). PEEP dependencies of airway and tissue properties were interpreted in terms of physiological phenomena such as airway closure and airway-parenchymal interdependence forces. In adult animals, Zrs was fitted to a model including a Newtonian resistance (R) in series with a constant-phase tissue compartment. In general, rodent respiratory parameters obeyed the same scaling laws described in other species, but rabbits had a relatively higher elastance than one would predict from previously published allometric relationships. This is probably due to the rabbit's proportionately smaller airspace volume. R normalized to body weight was lower in smaller species suggesting that they have proportionately wider airways compared to larger animals. By using computer models of the asymmetric airway tree to estimate airway resistance (Raw), we confirmed that the larger of two isomorphic rodent species has relatively higher Raw. Moreover, we showed that both the airway dimensional scaling differences and the asymmetric arrangement of the individual airways are responsible for the relative differences in Raw between smaller and larger animals. Finally, in the developing rat, elastance and resistance normalized to lung weight decreased progressively with age, suggesting that intrinsic changes in the mechanical properties of the respiratory system occur with development. Parenchymal interdependence forces manifested themselves in animals as young as 10 days of age, with PEEP
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Beck, Jennifer 1968. "Effects of chest wall configuration and electrode positioning on human diaphragmatic EMG." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=22536.
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The measurement and analysis of the human diaphragm electromyogram (EMGdi), as obtained with an esophageal electrode, requires objective control of the disturbances and filtering effects which can influence the signal. One issue of importance is that an increase in the muscle-to-electrode distance (MEdist) acts as a low-pass filter, filtering out the high frequency components of the EMG power spectrum (the MEdist filter). Due to the numerous factors which can influence the EMGdi, control of signal quality is also of utmost importance. The aims of this study were: (1) to evaluate the effect of the MEdist filter on EMGdi, as measured with a multiple array esophageal electrode, (2) to take advantage of the MEdist filter in order to locate the position of the diaphragm with respect to the electrodes, and (3) to evaluate the influence of changes in chest wall configuration on EMGdi center frequency (CF) values, while controlling for both signal quality and the MEdist filter.Five normal male subjects performed static contractions of the diaphragm at seven predetermined chest wall configurations. The EMGdi was measured with an array of eight steel rings mounted on a catheter, forming seven sequential pairs of electrodes, with an interelectrode distance of 10 mm. EMGdi signal quality was evaluated by computer algorithms. The pair of electrodes whose EMGdi signals (and power spectrums) were the least influenced by the MEdist filter was assumed to be closest to the diaphragm.
The results of the study indicated (1) EMGdi power spectrums and their associated CF values were strongly affected by the position of the diaphragm with respect to the multiple array esophageal electrode. CF decreased by approximately 1 Hz per mm displacement away from the diaphragm. (2) By controlling for the MEdist filter, there was no relationship found between changes in chest wall configuration and CF values. These data demonstrate that changes in chest wall configuration, and hence diaphragm length, do not influence the CF values of the EMGdi, if the distance between the electrodes and the diaphragm and signal quality are controlled for.
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Krogh-Madsen, Trine. "Effects of single-channel noise on spontaneous beating and the phase-resetting response of cardiac oscillators." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85562.
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From our everyday life, we know that our hearts beat with a rhythm which is not perfectly periodic. Even an isolated spontaneously beating cardiac cell, devoid of neural, hormonal, and intracardiac regulatory input, does not beat perfectly regularly. I investigate the hypothesis that the beat-to-beat fluctuations in transmembrane potential of spontaneously beating cardiac cells are due to stochastic gating of the ionic channels in the cell membrane.Recordings of transmembrane potential from small clusters of spontaneously beating 7-day-old embryonic chick ventricular cells were analyzed to characterize the voltage waveform and the regularity of beating. I constructed a deterministic Hodgkin-Huxley-type ionic model which reproduces spontaneous activity in our experimental recordings, as well as the experimental results of applying various ion channel blockers (D-600, almokalant, and Ba2+). The model consists of six currents: a calcium current (ICa), three potassium currents (IKs, I Kr, IK1), a background current ( Ib), and a seal-leak current (I seal).
The deterministic Hodgkin-Huxley-type model was then reformulated into a stochastic single-channel model. The single-channel model reproduces the irregularity of beating seen experimentally: e.g. the coefficient of variation of interbeat interval was 4.4% vs. 3.9% in the clusters. In the model, IKs is the current giving the major contributions to fluctuations in interbeat interval.
Phase resetting of the spontaneous activity of cardiac pacemaker cells by a brief stimulus pulse was simulated in Hodgkin-Huxley-type models and single-channel models of slow-upstroke (central) and fast-upstroke (peripheral) rabbit sinoatrial node cells. In the Hodgkin-Huxley-type models the phase-resetting response is continuous, but can be extremely delicate in the fast-upstroke model, in that a tiny difference in the stimulus timing can change the stimulus response from a delayed action potential to an advanced one. Therefore, the noise in the fast-upstroke single-channel model can cause a stimulus with fixed amplitude and fixed timing to have widely different effects: sometimes it will induce an action potential but in other cases it will delay an action potential, as seen previously in experiments on cardiac preparations.
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Lewis, Timothy J. "Modeling conduction in the ventricles." Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=60501.
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Two models of electrical conduction in the cardiac ventricles are considered. The first model considered is that of a strand of ventricular muscle which uses the one-dimensional cable equation with the Beeler-Reuter model to represent the transmembrane currents. The effect of periodic stimulation on the strand is numerically simulated, and it is found that as simulation frequency is increased, the rhythms of synchronization are successively encountered. It is shown that this sequence of rhythms can be accounted for by considering the response of the strand to premature stimulation. This involves deriving a one-dimensional finite-difference equation or "map" from the response to premature stimulation, and then iterating this map to predict the response to periodic stimulation.The second model states that the highly ramified His-Purkinje system is reminiscent of a fractal branching structure, and that the ventricular myocardium is activated in a "fractal" (time-scale invariant) fashion, since it is activated via the His-Purkinje system. A 1/$f sp alpha$ power spectrum can sometimes be linked to fractal processes. The averaged power spectrum of single QRS complexes falls off as 1/$f sp alpha$ ($ alpha sim$ 4).
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Liu, Qingde 1963. "Molecular and physical determinants of fibrinogen-dependent platelet aggregation and adhesion in flow." Thesis, McGill University, 1998. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=35909.
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Fibrinogen (Fg) mediates platelet aggregation and adhesion to artificial surfaces by interacting with its receptor, glycoprotein IIb and IIIa complex (GPIIbIIIa, or integrin alphaIIbbeta 3), on the platelet membrane. Considerable evidence has demonstrated that the (H12) on the gamma chain carboxyl terminus is required for the binding of Fg from solution to activated platelet GPIIbIIIa, while the RGD sites, the universal integrin recognition domain on adhesive ligands, are not involved. In this study, using recombinant Fg, well-defined Fg plasmin digestion fragments, and specific monoclonal anit-Fg antibodies, we demonstrated that the same sequence, the H12, or more precisely, the AGDV on the extreme carboxyl terminus of the gamma chain (gamma408--411), is also required for platelet-bound Fg to support platelet aggregation (crosslinking), thus experimentally verifying the "two sticky ends" theory of Fg-mediated platelet aggregation The RGD-containing domains on the Aalpha chains are not involved in aggregation. The AGDV sequence on the gamma chain carboxyl terminus is also necessary and sufficient for activated platelets to adhere to surface-adsorbed Fg, while the RGD sequences we similarly not required. A receptor induced binding site (RIBS), the Fg RIBS-I site (gamma373--385), on Fg either bound to its GPIIbIIIa-receptor or on a surface, is not directly involved in interactions between platelet GPIIbIIIa and immobilized Fg. The inhibitory effects of the anti-Fg-RIBS-I antibody are due to steric hindrance of the accessibility of the AGDV site to platelet GPIIbIIIa. Thus, the extreme carboxyl terminus of the gamma chain is the only site in both fluid and solid phase Fg that is involved in platelet GPIIbIIIa-Fg interactions.Though resting platelets are able to adhere to surface-bound Fg, this adhesion efficiency is much lower than that of the adhesion of the activated platelets. The adhesion efficiency of both resting and activated platelets to surface-adsorbed Fg decreases with increasing shear rate from 100 s -1 to 2,000 s-1. However, the decrease of the adhesion efficiency of the resting platelets is more marked than the decrease of the adhesion efficiency of the activated ones. Thus, the higher the shear rates, the larger the difference in the adhesion efficiencies between resting and activated platelets. However, due to the higher collision frequencies at higher shear rates, the adhesion of resting platelets was maintained at a similar level from shear rates of 300--2,000 s-1, while the adhesion of activated platelets kept increasing from 100 s -1 to 2,000 s-1. These data indicate that platelet activation is an efficient regulation pathway for platelet adhesion to surfaces.
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Walker, Angela. "Electrochemical study of vesicular release in bovine chromaffin cells." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=23431.
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The time course of the spontaneous current spikes produced by the release of the catecholamines from individual vesicles was examined in bovine chromaffin cells by using the carbon filament technique in the amperometric mode.Frequency histograms of the rise and decay times of the current spikes showed a paucity of very short duration events. Scatterograms of the rise and decay times consistently showed a positive relation, and the best fitted lines intercepted the ordinate (the axis of the decay time) at: 16.06 $ pm$ 6.45 msec (n = 11).
The effect of temperature changes upon the time course of release of content of individual vesicles in chromaffin cells was also examined. The amplitudes of the current spikes did not change significantly, whereas the rise times and the decay times diminished from (23.2 $ pm$ 11.6 to 11.9 $ pm$ 2.7 msec, and from 76.6 $ pm$ 25.4 to 47.3 $ pm$ 9.3 msec respectively) as the temperature was raised from 15$ sp circ$C to 35$ sp circ$C (n = 5). Nevertheless, the Q$ sb{10}$ values of the rise and decay times were surprisingly low.
The experimental findings suggest that in bovine chromaffin cells the duration of the release of content of single vesicles is much longer than in synapses. The results also suggest that this mechanism does not involve processes that are strongly temperature sensitive.
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Young, Richard N. (Richard Norman). "The effect of muscle contractility on surface EMG /." Thesis, McGill University, 1989. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=60423.
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This study was designed as an investigation of the role of changes in muscle force and changes in muscle length on the EMG for the Tibialis Anterior (TA).Using surface electrodes we examined the EMG for 4 contraction levels at 5 ankle positions over 60$ sp circ$ of ankle rotation. The change in median frequency with muscle length identified a significant shift in the power spectrum to lower frequencies with increasing muscle length.
To further investigate our results we performed three other experiments: First, using X-rays to identify the relative change in distance between two intramuscular wire electrodes we found the change in TA muscle length for this study to be 15% over the 60$ sp circ$ of ankle rotation. Second, to test for synergist contamination we used fine wire electrodes in the Extensor Digitorum Longus and the Peroneus. We found no evidence to support significant contamination. Third, we examined the role of smaller electrodes with a smaller interelectrode distance on our findings. The EMG showed drastic changes with even a slight shift in electrode position most likely due to the large number of innervation zones.
Therefore, the results indicate a shift in the power spectrum with a change in muscle length. In addition, surface EMG results are heavily dependent on the innervation zones and on the electrode geometry, all of which are important considerations in developing the EMG as an accurate diagnostic tool.
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Deng, Xiaoyan. "The effects of disturbed flows on mass transfer to and from an arterial wall /." Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=70234.
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The effect of disturbed flows on mass transfer to and from an arterial wall was studied both theoretically and experimentally using an idealized model of arterial stenoses in which an annular ring vortex was formed. It was found that the transport of macromolecules, including low density lipoproteins, from flowing blood to a semi-permeable vessel wall is greatly enhanced in regions of disturbed flow with a local maximum locating around the reattachment (stagnation) point. The surface concentration of macromolecules increases with increasing the filtration velocity and decreasing the flow rate. The disturbed flows also facilitated the transport of low molecular weight substances such as biochemicals but not macromolecules from arterial walls to flowing blood. These results strongly suggest that disturbed flows with slow recirculation flow provide favorable conditions for the genesis and development of atherosclerotic lesions by affecting local mass transport phenomena at the blood-vessel wall boundary.
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Chen, Yuejin. "Characterization of the Vasoactivity of Tachykinins in Isolated Rat Kidney: Functional Studies and in Vitro Receptor Autoradiography." Digital Commons @ East Tennessee State University, 1994. https://dc.etsu.edu/etd/2892.
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Although tachykinins have potent vascular actions, their effect on renal resistance blood vessels is currently unknown. The vasoactive properties of tachykinins and related analogs were assessed in isolated perfused rat kidney. At a basal perfusion pressure (PP) of 75 $\pm$ 6 mm Hg (n = 5), bolus injections of substance P (SP) had no significant vasoactive effect. Following a sustained increase in baseline PP (134 $\pm$ 10 mm Hg) produced by phenylephrine (1 $\mu$M), SP evoked a dose-dependent increase in PP. The largest dose of SP increased PP by 60 $\pm$ 5 mm Hg. The vasoconstrictor response to SP was not blocked by phentolamine when angiotensin II was used to increase basal tone. Thus, the response to SP is not mediated by norepinephrine. Pressor responses to SP were not potentiated by peptidase inhibitors, captopril and thiorphan. SP(1-7) had no effect on PP, suggesting that the pressor response to SP is C-terminal dependent and tachykinin receptor mediated. The selective NK-1 receptor agonist, (Sar$\sp9$,Met(O$\sb2)\sp{11}\rbrack$SP, had no effect on PP. In contrast, both the selective NK-2 and NK-3 receptor agonists, GR-64349 and (MePhe$\sp7$) NKB, produced dose-dependent pressor responses (116 $\pm$ 8 and 134 $\pm$ 15 mm Hg increases in PP at 33 nmol, respectively) and were more potent than SP. Infusion of capsaicin (500 nM) produced an initial increase in PP following by a more prolonged decrease in PP. Clamping the renal vein produced a marked increase in PP. The localization of NK-3 receptors in rat kidney evaluated by film autoradiography using $\sp{125}$I- (MePhe$\sp7\rbrack$NKB revealed a high density of specific binding sites on the proximal ureter and renal pelvis, moderate density in the renal vein and its large branches, and a low density in the inner strip of outer medulla, but no specific binding on the renal artery system and cortex. High resolution autoradiograms demonstrated $\sp{125}$I- (MePhe$\sp7\rbrack$NKB binding sites on the tunica media of the renal vein and tunica muscularises of renal pelvis and ureter. Specific binding of $\sp{125}$I-BHSP was found in association with the renal artery and renal pelvis. No specific SP binding sites were associated with renal vein. These data indicate that the pressor effect of tachykinins in the isolated rat kidney can be mediated by NK-2 and/or NK-3 receptors. The latter may be on the vascular smooth muscle of the renal vein.
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He, Dingsheng. "Connexins 40 and 43 form heteromeric gap junction channels in vascular smooth muscle cells." Diss., The University of Arizona, 1999. http://hdl.handle.net/10150/284991.
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Gap junction channels connect the cytoplasms of adjacent cells and provide a pathway for the exchange of materials between cells. The nature of the materials exchanged is determined by the biophysical characteristics of the channels. The functional gap junction channel is composed of paired hemichannels (connexons) from each cell. Connexons are hexamers of protein subunits called connexins (Cx). Of the 15 connexin genes found in the mammalian genome, the products of only two, Cx40 and Cx43 have been localized in vascular smooth muscle cells (SMC) (1;2). We have been interested in identifying the role of gap junctions in cardiac rhythmic activity and vascular function. Like many other cell types, mammalian heart and blood vessels express multiple gap junction connexins (3). These connexins may form heteromeric channels. A7r5 cells, a cell line derived from embryonic rat aortic smooth muscle cells, provide a good model because they express both connexins 40 and 43. From the previous studies in this laboratory, Moore and Burt reported the presence of channels with a wide range of unitary conductance with major peaks at 75, 110 and 145 pS. One explanation for the wide range of unitary conductance could be the presence of heteromeric Cx40 and Cx43 channels. Thus, the goal of this study was to investigate gating behaviors of gap junction channels in A7r5 cells to determine whether heteromeric Cx40/43 channels are formed. I will demonstrate that Cx40 and Cx43 form heteromeric channels with unique unitary conductances, voltage-dependent gating properties and enhanced sensitivity to halothane induced closure.
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Galloway, James Coleman. "Muscle torque-total torque relationships at the shoulder and elbow: Rules for initiating multijoint arm movements." Diss., The University of Arizona, 1998. http://hdl.handle.net/10150/282845.
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One concept central to theories of multijoint control concerns the selection of muscles for the appropriate joint motion. For multijoint movements, a given muscle torque at an individual joint can lead to flexion, extension, or very little motion, since mechanical effects coming from other segments interact with muscle torque. This study quantified the contribution of muscle torque to initial joint motion for horizontal arm movements throughout the workspace. Previous studies of arm mechanics have been limited to a few movements or have focused on one joint. In contrast, this study reports data for both the shoulder and elbow joints. Moreover, a large number of movements were used for which direction, excursion, and distance were manipulated. Using high speed video recordings and techniques of inverse dynamics, a ratio of muscle torque to total torque was computed for each movement as a measure of contribution of muscle torque to joint acceleration. One consistent finding was that the muscle torque contribution consistently differed between the shoulder and elbow for most of the workspace. At one joint, muscle torque directly contributed to acceleration with negligible interaction torque ('direct' muscle torque contribution), thus the joint appeared to act as the launcher of the arm. At the other joint, both muscle and interaction torques contributed to joint acceleration ('complex' contribution), thus the joint appeared to be responding to mechanical effects from motion of the launcher. This contrast between joints may provide a simplifying feature for multijoint arm control. Specifically, only one of the two joints has complex mechanics, while the other joint, surprisingly, has simplified mechanics similar to a single joint in isolation. Movements in this study also demonstrated a three fold covariance (muscle torque contribution, movement direction, and the relative excursions of the shoulder and elbow) regardless of distance. A covariance of movement features, historically viewed as a confound, may provide a further simplification for arm control by reducing the unknowns; namely, the muscle torque contribution is associated with a resultant direction and joint excursions, or a direction or set of excursions is achieved by the associated muscle torque contribution.
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Maksym, Geoffrey N. "Modelling lung tissue theology." Thesis, McGill University, 1997. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=42087.
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A model was developed to account for the static elastic behaviour of the lung tissue strip in terms of distributions of collagen and elastin fibers. Distributions of collagen fiber lengths and elastin fiber stiffnesses were determined by fitting the model to data from dog lung tissue strips. These distributions followed 1/f power-laws for more than 95% of the data. Computer simulations of two dimensional tissue strip models with 1/f distributions of collagen fiber lengths also predicted realistic stress-strain curves. The simulations illustrated the gradual development of geometric and stress heterogeneity throughout the tissue as the collagen fibers were recruited during stretch. This model suggests a mechanistic basis for the shape of the pressure-volume curve of whole lung. It also indicates how this curve may be affected by changes in tissue collagen and elastin similar to the changes occurring in the diseases of pulmonary emphysema and fibrosis. Nonparametric block-structured nonlinear models for describing both the static and dynamic stress-strain behaviour of the lung were applied to dog lung tissue strips and to whole rat lungs in vivo. Both the Wiener and Hammerstein models accounted for more than 99% of the tissue strip data, although the Hammerstein model was more consistently accurate across a range of perturbation amplitudes and operating stresses. Plastic dissipation of energy within the lung tissue strip was estimated at less than 20% of the total dissipation during slow sinusoidal cycling. The Hammerstein model was also the best of those investigated for describing the rat lung data in vivo, although there were dependencies of the model parameters on perturbation amplitude and operating point that indicate that a more complicated model is required for the whole lung. Finally, construction of a fiber recruitment model for the dynamic mechanical behaviour of lung tissue strips was attempted. However accurate reproduction of measured behaviour was no
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Somasekharan, Suma. "NC-1059, a channel forming peptide, induces a reversible change in barrier function of epithelial monolayers." Diss., Manhattan, Kan. : Kansas State University, 2008. http://hdl.handle.net/2097/553.
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Malreddy, Pradeep Reddy. "Potassium channels support anion secretion in porcine vas deferens epithelial cells." Thesis, Manhattan, Kan. : Kansas State University, 2009. http://hdl.handle.net/2097/1463.
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Fouchard, Jonathan. "Relation entre forme, tension et adhésion au cours de l'étalement d'une cellule animale." Phd thesis, Université Paris-Diderot - Paris VII, 2012. http://tel.archives-ouvertes.fr/tel-00757194.
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Chaque cellule d'un animal possède le même génome. Pourtant, ces cellules peuvent avoir des formes et des phénotypes très différents. Or, il a été démontré que l'environnement mécanique peut influencer la forme et même le phénotype cellulaire. On peut donc se demander comment une cellule acquiert une forme, et quelle place joue l'environnement mécanique dans ce processus. Dans cette thèse, nous avons étudié l'étalement précoce de fibroblastes, événement au cours duquel ces cellules passent d'une forme sphérique, où aucune tension n'est transmise au substrat, à une forme étalée, où les cellules compriment le substrat en transemttant leur tension interne à travers des agrégats de protéines que l'on nomme complexes d'adhésion. Afin de déterminer comment la formation de ces complexes corrèle avec la tension tranmise au substrat pendant l'étalement, nous avons mis au point un dispositif capable de mesurer les forces de traction cellulaire en géométrie uniaxiale et d'imager la réorganisation des complexes d'adhésion. Ainsi, nous avons pu montrer que lorsque l'étalement est rapide, la force est nulle et aucun complexe d'adhésion n'est formé. Puis la force commence à croître suivie des adhésions, tandis que l'étalement se fait plus lent. La transition entre ces deux phases semble gouvernée par un changement de forme du corps cellulaire lorsque l'angle qu'il forme avec le substrat dépasse 90°. Nous avons ensuite cherché à savoir comment l'environnement mécanique des cellules pouvait affecter ce scénario en faisant varier la raideur de notre senseur de force, puis en comparant la forme du contact adhésif lorsque la cellule s'étale sur une plaque et entre deux plaques.
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Yan, Dejun. "THE EFFECT OF CURCUMIN ON LEWIS LUNG CARCINOMA." Bowling Green State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1308588440.
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Anderson, Ross William. "Subthreshold Oscillations and Persistent Activity Modulate Spike Output in the Rodent Dentate Gyrus." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1415229722.
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Maillett, David H. "Engineering hemoglobins and myoglobins for efficient oxygen transport." Thesis, 2004. http://hdl.handle.net/1911/18666.
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Consumption of the intercellular messenger, nitric oxide (NO), by extracellular hemoglobin causes the hypertensive side effect associated with current blood substitute products. Substitution of large aromatic amino acid side chains into the distal cavity of hemoglobin can decrease the rate of this NO scavenging reaction, and mitigate the hypertensive effect. However, such substitutions can also affect O2 binding and release by hemoglobin. To better define the impact of distal pocket mutation on O2 transport, several myoglobin prototypes were tested in an artificial capillary. In addition, a series of recombinant hemoglobins containing phenylalanine and tryptophan substitutions at key locations were characterized to examine how these mutations affect O2 and CO binding.
Experiments measuring O2 release and uptake by mutant myoglobins in an artificial capillary demonstrate that delivery is dependent on the affinity of the protein, but that uptake is similar for all of the mutants. This shows that decreases in association rate constants are better tolerated than decreases in dissociation rate constants, and validates the connection between the equilibrium constant for O2 binding, and the physiological transport function of hemoglobin.
Placement of Phe and Trp at positions B10, E11 and G8 within the distal pocket decreases the rate at which ligands can gain entry to the active site, which was expected based on similar behavior in myoglobin mutants. The B10 mutants have direct steric and electrostatic interactions with the ligand, seen in the 2000-fold decrease in rate of O2 association for the beta(Trp(B10)) and 60-fold decrease in the O2 dissociation rate constant for alpha(Phe(B10)) subunits. Substitution at position E11 increases O2 and CO affinity due to removal of the naturally occurring gamma2CH3 group of Val(E 11). The E11 mutants have less dramatic effects in hemoglobin than in myoglobin due to the absence of 'extra' volume in the back of the distal cavity in either hemoglobin subunit. Steric crowding by position G8 mutants decreases the rate and extent of ligand capture, particularly in beta subunits. In general, ideas developed for ligand binding in myoglobin translate well to hemoglobin, but structural details of each subunit can magnify or diminish the effect of the mutation.
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Whitby, Frank G. "Structure of tropomyosin at 7A resolution." Thesis, 1995. http://hdl.handle.net/1911/16897.
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The crystal structure of tropomyosin has been determined by X-ray diffraction analysis at 7A resolution. Tropomyosin is a 400A-long muscle regulatory protein that consists of two parallel 33,000 Dalton alpha helices wound around one another to form a coiled coil and whose amino-acid sequence is characterized by a characteristic heptad repeat pattern. The structure was solved initially at 9A resolution by molecular replacement and refinement of a uniform wire model with a specially designed refinement procedure. Phase information was later derived from a single mercury derivative by single isomorphous replacement (SIR) refinement and used in the construction of an atomic model which was refined at 7A resolution.
The model agrees well with the previous low-resolution X-ray structure and with models of tropomyosin in paracrystalline and micro-crystalline forms based on electron microscopy. The overall shape of the molecules, characteristics of the coiled coil and the geometry of interactions of molecules in the crystal are apparent from the structure. The molecules are precipitated by spermine and polymerize head-to-tail to form sheets of nearly parallel filaments, overlapping by about 2/3 of the molecular length in an antiparallel configuration. The relationship of two cysteine residues on each of the molecules was determined unambiguously by solving the structure of a mercury-labeled form of the protein. The shape of the molecule is influenced by local amino-acid sequence variations and crystal packing interactions. The inherent mobility of the molecule in the crystal indicates the importance of considering the flexibility and motions of tropomyosin in models of muscle thin filament regulation and cooperativity. The detailed structure of the head-to-tail overlap region cannot be ascertained from the present model, but will be an important focus of attention for future study.
Through amino-acid sequence analysis, an element of quaternary structure, the coiled coil, can be directly predicted. However, tropomyosin is the largest of this class of proteins whose structure has actually been determined by X-ray crystallography.
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Lindblad, Douglas S. "A model of the rate dependence of the atrial action potential in rabbit." Thesis, 1994. http://hdl.handle.net/1911/13859.
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We have developed a mathematical model of the rabbit atrial myocyte in order to investigate the ionic bases of rate dependent changes in action potential (AP) wave-shape. Postulated mediators of such changes include rate dependencies of ionic currents (incomplete reactivation) and ionic concentration gradients. The model utilizes biophysical data to quantify the specific morphology and electrophysiology of the rabbit atrial cell. Ionic current descriptions incorporate whole-cell voltage-clamp data from enzymatically isolated rabbit cardiomyocytes, and account for the reactivation timecourse of the largest ionic currents. Our model can simulate both the whole-cell voltage-clamp data upon which it is based and the steady-state AP wave-shapes observed over a range of stimulus rates. It also predicts the intracellular $\lbrack Ca\sp{2+}\rbrack\sb{i}$-transient that accompanies the AP, the "premature stimulus" response, and the effect of rapid stimulation on the AP. These responses provide insight into the electrophysiological mediators of atrial refractoriness and arrhythmia.
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Shumaker, John Michael. "Conduction in a bullfrog atrial trabeculum: Active and passive properties, and modifications produced by acetylcholine." Thesis, 1992. http://hdl.handle.net/1911/16547.
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A model of $\beta$-adrenergic and muscarinic cholinergic stimulation of the bullfrog atrial myocyte has been developed that mimics the dose-dependent effects of isoprenaline (ISO) on the action potential duration (APD); i.e., low doses of ISO lengthen the APD, while high doses shorten the ADP. This reduction in APD is modeled as the result of (1) calcium-dependent inactivation of $I\sb{Ca}$ resulting from the enhancement of $I\sb{Ca}$ by ISO and (2) an enhancement of $I\sb{K}$ due to both an ISO-induced increase in the rate of activation of $I\sb{K}$ and an increase in peak action potential height. The effect of acetylcholine (ACh) is to reduce the ISO-induced increase in $I\sb{Ca}$ and $I\sb{K}$ through a reduction in relative (cAMP) as well as to stimulate the ACh-sensitive $K\sp{+}$ current $I\sb{K,ACh}.$ At low (ISO) levels or high (ACh) levels, the muscarinic cholinergic effect dominates over the $\beta$-adrenergic effect. However, for a large (ISO) and a small (ACh), this pattern of changes in transmembrane currents is different; in this case the model predicts that ACh can actually increase APD.
A distributed parameter model of an idealized bullfrog atrial trabeculum is developed. Individual cardiac cells are resistively coupled end to end via intercalated discs to form an idealized cylindrical cardiac strand encased in a resistive-capacitative trabecular sheath which, in turn, is located in a finite cylindrical volume conductor. A second-order implicit finite numerical integration method is used to calculate the time-varying potentials within the intracellular $(V\sp{i}),$ interstitial $(V\sp{e}),$ and the outer volume conductor $(V\sp{o})$ media of the concentric cylindrical structure. 'Reduced' cell membrane models which lack the complete complement of transmembrane currents are compared with regard to their accuracy in representing the foot, upstroke, and plateau regions of the propagated action potential in the complete model. A reduced cell membrane model should contain the sodium current $I\sb{Na},$ the calcium current $I\sb{Ca}$ and the background rectifying $K\sp{+}$ current $I\sb{K1}.$ A cell membrane model which contains a linear background $K\sp{+}$ current $I\sb{L}$ instead of $I\sb{K1}$ produces a poor approximation to the upstroke, plateau and conduction velocity of an action potential. The trabecular sheath reduces the extracellular resistance seen by the cell by shunting current away from highly resistive interstitial medium into the volume conductor medium which is of low resistance, and thereby increases conduction velocity. Finally, the effects of the cholinergic neurotransmitter, acetylcholine (ACh), on both the passive and active properties of the trabeculum are investigated. The addition of ACh to the extracellular medium reduces the space constant and input resistance of the trabeculum, as well as the conduction velocity of electrical activity propagating through it.
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Cates, Mary Susan. "Crystallographic and computational studies of the metal ion binding properties of parvalbumin." Thesis, 2000. http://hdl.handle.net/1911/19477.
Full textAbstract:
An astonishing number of important physiological processes are regulated by the small alkaline earth metal, calcium. Regulatory Ca2+-binding proteins must be able to distinguish Ca2+ ions in the presence of greater concentrations of other metal cations, such as Mg2+, Na+ and K+. The EF-hand family is a large class of Ca2+-binding proteins that displays this sort of preferential Ca2+-binding. The secondary and tertiary structure of the EF-hand metal ion binding site is highly conserved from one member of the family to the next. Because of this conservation, we can use the small, amenable, EF-hand protein, parvalbumin, as a model system to study the mechanisms that define the metal ion affinities and specificities of EF-hand Ca2+-binding sites in general.
Our collaborator, Dr. James Potter, has designed a mutant to test directly the role of the last coordinating residue in the EF-hand binding site, the PVEF-E101D parvalbumin mutant. The crystal structures of both the Ca 2+- and Mg2+-bound complexes of PVEF-E101D have been determined. The PVEF-E101D mutant displayed a 100-fold decrease in the binding affinity for Ca2+, and the Mg2+-binding affinity was increased 10-fold. Moreover, the Ca2+ off-rate escalated from 1 s--1 in wild-type parvalbumin to 600 s--1 in the PVEF-E101D mutant. The conformation of the mutated EF-hand in the PVEF-E101D/Mg2+ structure was typical of a Mg 2+-bound EF-hand, with the exception of an F helix movement of ∼1 A toward the bound cation that allowed the shorter aspartate residue to coordinate the Mg2+ ion. The PVEF-E101D/Ca2+ structure showed that the aspartate residue is unable to bind Ca2+ in the bidentate mode normally adopted by the wild type glutamate. The resulting sixfold Ca2+ coordination in the mutant is usually characteristic of Mg2+-bound EF-hands, and this finding indicates that the binding loop is not sufficiently flexible to allow the aspartate residue to move in far enough to offer bidentate ligation of the Ca2+ ion.
Two MD simulations were used to further investigate the relationship between the last coordinating residue of the EF-hand binding loop and the overall plasticity and flexibility of the loop region. The first simulation, called Alchemy, simulated the transition from Ca2+ to Mg 2+ coordination through varying the van der Waals parameters for the bound metal ions. The glutamate at position 12 was accurately and reversibly predicted to be the source of bidentate ligation of Ca2+ in our simulations. A second simulation, the Aspartate simulation, produced results that correlated well with the experimental result that an E101D substitution at EF loop position 12 resulted in monodentate Ca2+ coordination. The F helix was able to move in to the binding cavity during the simulation to allow one aspartate oxygen to bind the Ca2+ ion, but the aspartate was unable to achieve a favorable orientation for bidentate Ca 2+ coordination. The findings indicate that the interplay between the last coordinating residue of the loop, and the plasticity, or flexibility, of the binding loop, to a great extent determines the species of cations that are allowed to bind in a particular EF-hand site.
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Lu, Kun. "Human whole-body gas exchange and cerebral autoregulation studied using a cardiopulmonary model." Thesis, 2004. http://hdl.handle.net/1911/18665.
Full textAbstract:
The goal of this work is to study human whole-body gas exchange and cerebral autoregulation using a mathematical model. Previously, a human cardiopulmonary (CP) model [45, 47] was developed, which included heart, closed-loop blood circulation, gas exchange at lungs and baroreflex control of arterial pressure. In the current study, two major extensions to the model are made. First, a description of gas exchange in the peripheral tissues is added and is coupled with the lung gas exchanger via the circulatory loop with variable transport delays. A peripheral chemosensitive loop is also added to mimic the influence of blood gas composition on the heart and vasculature. The CP model is then used to predict the integrated cardiovascular and blood-tissue gas transport responses to pronounced changes in lung gas composition, and thus simulates changes encountered in apnea with and without passive oxygenation. The second extension of the CP model includes a more detailed description of cerebral circulation, cerebrospinal fluid (CSF) dynamics, brain gas exchange and cerebral blood flow (CBF) autoregulation. Two CBF regulatory mechanisms are described: autoregulation and CO2 reactivity. Central chemoreceptor control of ventilation is also added. This new model is subsequently used to study cerebral hemodynamic and brain gas exchange responses to test protocols commonly used in the assessment of CBF autoregulation (e.g., carotid artery compression and the thigh cuff test). The model closely mimics the experimental findings and provides biophysically based insights into the dynamics and interactions of the associated physiological systems. In summary, this work represents a bold effort in large-scale modeling of physiological systems. The presented model accurately describes the physiological systems and can explain how the cardiovascular, pulmonary and autonomic nervous systems interact in response to a variety of cardiopulmonary challenges, such as apnea, carotid artery compression and the thigh cuff test. With further refinement, the model may help investigators to better understand the complex biophysics of cardiopulmonary diseases such as sleep-related disorders of breathing (obstructive and central sleep apnea) and complications associated with head-injuries.
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"The elastic properties of the human mandible." Tulane University, 1989.
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This dissertation is a report on a study of the elastic properties of the human mandible. Using a pulse transmission technique, it was determined that the elastic stiffness 76 specimens, from various locations in the ramus and corpus of four mandibles material exhibited symmetry properties which were characteristics of anisotropic material In order to facilitate an understanding of the coordinate system used in determining the elastic stiffnesses of the specimens, a simplistic model can be employed. Assume that a section of the human mandible is projected point-by-point on to a straight line with the left wisdom tooth at one extreme, and the right wisdom tooth at the other Now consider this projection of the mandible to approximate a right circular cylinder. The x$\sb3$-direction is defined to be along the length of the cylinder, axial direction. The circumferential direction is designated by x$\sb2$ and the radial by x$\sb1$ The similarity between mandibular and femoral bone is quite remarkable. Femoral bone is slightly more dense and stiff, but the similarities far outweigh the differences. The average density of mandibular bone is 1799 kg/m$\sp3$ 95% of that of femoral bone. The average stiffness coefficient for mandibular bone is 96% of that of femoral bone. It would appear from this comparison that the mandible is in its elastic properties very much like a long bone bent in the shape of a parabola. The average technical constants for mandibular and femoral bone show a distinct parallelism It was determined from a study of the human mandible by region that the lingual region, surface in the proximity of the tongue, is most dense and stiff while the buccal, surface nearest the cheek, is the least stiff. Similarly, it was found that average specimens from mandibles with teeth were denser and stiffer than those from mandibles without teeth. (Abstract shortened with permission of author.)acase@tulane.edu
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"Sympathetic neurotransmission in primary hypertension." Tulane University, 1992.
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Extracellular compound action potential recordings revealed that transmission of physiological rates (1-5 Hz) of preganglionic nerve impulse activity through superior cervical ganglia (SCG) is enhanced in spontaneously hypertensive rats (SHR), the animal model of genetic hypertension used in these studies. Further studies indicated that these same ganglia have a diminished ability to transmit high frequencies ($>$70 Hz) of nerve activity Intracellular EPSP and EPSC recordings from single SCG neurons suggest that the enhanced impulse transmission observed in these ganglia results from an increase in transmitter release by the preganglionic nerve terminals innervating postganglionic SCG neurons. This increased transmitter release results in an elevated EPSP amplitude thereby increasing the efficacy of impulse transmission in SHR sympathetic ganglia. The increased transmitter release also depletes a similarly sized immediately releasable transmitter store to a greater extent in the hypertensive rats when compared to normotensive controls. The enhanced transmitter depletion diminishes the amount of short-term facilitation and enhances synaptic depression, limiting the ability of SHR preganglionic neurons to increase transmitter release during repetitive stimuli. These difference are hypothesized to play a role in the previously mentioned relative inability of SHR ganglia to transmit high frequency nerve impulse activity Whole-cell voltage-clamp recordings from acutely isolated SCG neurons revealed that postsynaptic membrane sensitivity to ACh, and the time course of ACh action are the same in SHR and normotensive controls, suggesting that postganglionic alterations do not play a role in the altered impulse transmission observed in SHR sympathetic ganglia The enhanced ability of SHR sympathetic ganglia to transmit physiological rates of preganglionic nerve activity would result in a greater amplification of preganglionic nerve activity in SHR ganglia, when compared to normotensive controls. This amplification of sympathetic nerve activity would directly contribute to the maintenance of hypertension in this animal model, and may be representative of cellular alteration(s) that are responsible for the enhanced sympathetic nerve activity observed in the SHR. Therefore, these studies further implicate an exaggerated sympathetic nerve activity in the pathogenesis of hypertension in the SHR model and reveal that an alteration of synaptic transmission could underlie the increased nerve activityacase@tulane.edu
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Nygren, Anders. "Mechanisms of repolarization and conduction in a mathematical model of electrophysiological responses in the human atrium." Thesis, 1998. http://hdl.handle.net/1911/19297.
Full textAbstract:
We have developed a mathematical model of the human atrial myocyte, based on averaged voltage-clamp data recorded from isolated single myocytes. This formulation can reconstruct action potential data which are representative of recordings from a majority of human atrial cells in our laboratory, and therefore provides a biophysically based account of the underlying ionic currents. This work is based in part on a model of the rabbit atrial myocyte, and was motivated by differences in some of the repolarizing currents between human and rabbit atrium. We have therefore given particular attention to the sustained outward $K\sp+$ current, $I\sb{sus}$, which putatively has a prominent role in determining the duration of the human atrial action potential. Our results demonstrate that the action potential shape during the peak and plateau phases is determined primarily by $I\sb{t}$, $I\sb{sus}$, and $I\sb{Ca,L}$, and that the role of $I\sb{sus}$ in the human atrial action potential can be modulated by the baseline sizes of $I\sb{Ca,L}$, $I\sb{sus}$, and $I\sb{K,r}.$ As a result, our simulations suggest that the functional role of $I\sb{sus}$ can depend on the physiological/disease state of the cell.
We have furthermore used our single-cell model to formulate a multicellular model of one-dimensional propagation in an idealized human atrial strand. Three different formulations for this model was explored: the classical cable equations with fixed ion concentrations, an "electrodiffusion" formulation which accounts for variable ion concentrations due to axial and radial transport, and an intermediate cable equation formulation which accounts for variable ion concentrations due to radial transport only. Comparative simulations show that the variable-concentration cable equation formulation can accurately simulate ion concentration dynamics during propagation, and therefore provides a less computationally demanding alternative to the electrodiffusion formulation. Simulations using the multicellular model predict that conduction velocity in the human atrium has a similar dependence on extracellular $\lbrack K\sp+\rbrack$ as in ventricular cells, including a region of "supernormal conduction" at moderate $\lbrack K\sp+\rbrack\sb{o}$-elevations, but that this response spans a smaller range of conduction velocities in the atrium. Our results suggest that this difference can he explained in terms of the smaller $I\sb{K1}$, and higher input resistance, of atrial cells.
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Ramasubramanian, Anand. "Characterization of platelet glycoprotein Ib-IX-V: von Willebrand factor interaction under shear conditions." Thesis, 2004. http://hdl.handle.net/1911/18686.
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Arterial thrombosis is one of the important pathophysiological mechanisms that lead to cardiovascular diseases. In this thesis, we have made an attempt to better characterize the kinetic and molecular mechanisms that underlie the critical first step in arterial thrombosis, namely, the interaction between platelet glycoprotein (GP) Ib and von Willebrand factor (VWF).
In the first part of the work, we evaluated the kinetics of interaction between platelet GP Ib-IX-V complex and VWF under arterial flow conditions. The GP Ibalpha subunit of GP Ib complex binds to VWF through the Al domain of VWF. Impaired GP Ib-VWF interaction due to GP Ibalpha mutations can result in bleeding abnormalities including platelet-type von Willebrand disease (ptVWD). We measured the cellular on- and off-rate constants of CHO cells expressing wild-type or gain- or loss-of-function mutant GP Ibalpha interacting with VWF-Al-coated surfaces at different shear stresses. We found that the gain-of-function mutant, K237V, rolled very slowly and continuously on VWF-Al surface while the loss-of-function mutant, Q232V, showed fast, saltatory movement compared to the wild-type (WT). The off-rate constants, calculated based on the analysis of lifetimes of transient tethers formed on surfaces coated with limiting densities of VWF-Al, revealed that the Q232V and K237V dissociated 1.25-fold faster and 2.2-fold slower than the WT. The cellular on-rate constant of WT, measured in terms of tethering frequency was 3-fold more and 3-fold less than Q232V and K237V, respectively. Thus, the gain- and loss-of-function mutations in GP Ibalpha affect both the association and dissociation kinetics of the GP Ibalpha-VWF-Al bond.
In the second part of the work, we compared the interaction of unusually large multimers of VWF (ULVWF) and that of the normal plasma multimers of VWF (P-VWF) platelets. ULVWF multimers are implicated in the pathology of a thrombotic disorder, thrombotic thrombocytopenic purpura (TTP) due to their increased affinity for platelets. We found that the ULVWF multimers are more effective than the normal P-VWF multimers in mediating (a) platelet aggregation in solution at high shear stress; (b) ristocetin-modulated platelet agglutination and (c) platelet adhesion to immobilized VWF under arterial shear conditions.
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Azizi, Emanuel. "Biomechanics of salamander locomotion." 2005. https://scholarworks.umass.edu/dissertations/AAI3179854.
Full textAbstract:
Most larval and permanently aquatic salamanders use undulatory swimming as their primary mode of steady aquatic locomotion. These swimming movements are powered by the segmented axial musculature. The hypaxial region of each segment consists of distinct muscle layers, which have a simple planar geometry and have varying architectural features. In an aquatic salamander Siren lacertina, the morphological features of the lateral hypaxial layers allow the shortening of muscle fibers to be amplified during contraction. The angled muscle fibers in these layers function to allow fiber shortening to be accompanied by substantial rotation of muscle fibers during contraction. The connective tissue sheets separating adjacent muscle segments (myosepta), allow the segment to bulge in a way that further amplifies muscle fiber rotation. The combined effect of architectural and moment arm variation ensures that muscle fibers from different layers undergo similar shortening patterns during swimming to allow for the generation of optimal tension during locomotion. In addition to steady swimming many salamanders respond to a predatory stimulus by performing a “C-start” aquatic escape response. This unsteady maneuver involves two kinematic stages, which function to propel the salamander away from the perceived threat. During metamorphosis, the tailfin of salamanders is resorbed and is thought to result in a substantial decrease in escape performance. However, in a stream salamander Eurycea bislineata , adults spend significant time in the water and behaviorally compensate for metamorphic changes in tail morphology by increasing the amplitude of escape responses. Aquatic locomotion in salamanders is not limited to axial swimming. Some salamanders also utilize their limbs to move along the substrate at slow speeds, while submerged. Structures used during aquatic walking face dramatically different mechanical loads compared to limbs used on land. The greater hydrodynamic resistance associated with water lowers the effective weight and can act to stabilize an organism throughout its gait. Therefore structures, such as the reduced limbs of S. lacertina, which would be considered ineffective on land, can be fully functional during aquatic walking.
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Li, Li. "The influence of the inertial properties of the human body: Cycling at different pedaling speeds." 1999. https://scholarworks.umass.edu/dissertations/AAI9932325.
Full textAbstract:
Human performance will be altered by changes in movement speed. The inertial properties of human limbs may play an important role in these alterations. The effects of these changes may be observed with the measurement of joint and segmental mechanics, as well as muscular kinematics, kinetics and muscular activity patterns. In this study, the cycling motion was used to investigate these inertial effects, following the development of a new mechanical model that provided the theoretical basis of coordination changes with movement speed. The alteration of cycling performance with different pedaling speed was examined using: (1) Surface EMG as an indication of the changes in muscular coordination as a function of cadence; (2) Inverse dynamics and decomposition of mechanical parameters to identify the influence of gravitational, inertial, and external factors; and (3) Simulations via a musculoskeletal modeling approach to assess the contributions of individual muscles. As predicted by the theoretical model, an increase in pedaling speed produced greater changes at the hip joint compared to knee and ankle joint in both muscular activities and mechanical measures. The changes in muscular activity were evident in both the activity of the single joint hip extensor and the coordination among the synergistic muscles. The altered muscular activities with increased cadence were accompanied by changes in joint moments, in the order of hip, knee and ankle joint from greatest to smallest. Further, the responses in movement organization were not linearly related to the increased inertial influence as the pedaling speed increased. Finally, the simulation analysis demonstrated a compensatory relation between gastrocnemius and soleus muscular activities with different pedaling speeds, although the combined patterns of the two were consistent.